Heart Rhythm

Effect of electrocardiographic lead placement on localization of outflow tract tachycardias

Elad Anter, David S. Frankel, Francis E. Marchlinski, Sanjay Dixit — 2011-12-12

Background: The origin of outflow tract ventricular tachycardia (OTVT) can be predicted from a surface electrocardiogram: indexes of R-wave amplitudes in leads V1 and V2 are used to differentiate a right origin from a left origin, while the axis of lead I differentiates an anterior origin from a posterior origin. Incorrect electrode placement is clinically common and may alter predictability of OTVTs. Objective: To explore the influence of vertical deviation in leads V1 and V2 and arm lead position on the QRS morphology of OTVTs. Methods: Vertical deviation of leads V1 and V2 was studied in 18 patients with OTVTs. Ventricular premature depolarization beats were recorded in the standard position, superior position, and inferior position. The effect of arm lead position was studied in a separate cohort of 16 patients: ventricular premature depolarizations were recorded with limb leads positioned over the shoulders and over the chest. The origin of tachycardia was determined by using activation mapping and confirmed by successful ablation. Results: Superior displacement of leads V1 and V2 reduced the R-wave amplitude and led to a decreased R/S ratio (0.11 ± 0.09 vs 0.17 ± 0.1; P <.01), while inferior displacement of leads V1 and V2 resulted in an increased R-wave amplitude and led to an increased R/S ratio (0.46 ± 0.35 vs 0.17 ± 0.1; P <.01). Anterior displacement of the arm leads from shoulders to chest resulted in the reduction in the R-wave amplitude in lead I (0.25 ± 0.30 mV vs 0.04 ± 0.43 mV; P <.05). Conclusions: Small changes in electrocardiographic electrode placement markedly alter the QRS morphology of OTVTs and thus alter the predictability of OTVT origin. These deviations are well within the range of clinical application and have the potential to misdirect ablation procedures.

Predictors of long-term success after catheter ablation of atriofascicular accessory pathways

2012-01-04

Background: Electrophysiologic characteristics, mapping strategies, and acute success rates of radiofrequency catheter ablation of atriofascicular accessory pathways are well described. However, data on long-term prognosis and predictors for freedom from arrhythmias are lacking. Objective: To report our 20-year single-center experience on ablation of atriofascicular fibers. Method: Between 1992 and 2010, 34 patients with atriofascicular accessory pathways underwent catheter ablation at our institution because of symptomatic antidromic atrioventricular reentrant tachycardias. Radiofrequency procedures were retrospectively analyzed, and patients were followed for recurrences of tachyarrhythmias. Electrocardiograms (before and after ablation and at follow-up) were analyzed for each patient. Results: Successful catheter ablation of the atriofascicular fiber was achieved in 23 (68%) patients. Mechanical block during mapping occurred in 3 (9%) patients, and in 2 of them ablation was performed at the site of mechanical block. Mere modification of conduction properties of the pathway without complete block was achieved in 5 patients (15%). Fast pathway ablation was performed in 2 (6%) of the patients ablated in the early 1990s. During follow-up of 9.3 ± 5.5 years, 24 patients (71%) remained free of tachyarrhythmias, 7 reported significant improvement, and 3 (9%) had no change in symptoms after ablation. Long-term success was identical between patients from the first (1992–1999) and second (2000–2010) decade (12 of 17 [71%] vs 12 of 17 [71%]). It was 87% in those with complete block of the atriofascicular fiber while all patients with mechanical block during mapping reported recurrences. Fast pathway ablation was complicated by complete atrioventricular block in 1 patient, who required pacemaker implantation 18 years after ablation owing to loss of conduction properties of the atriofascicular fiber over the years. On analyzing patients with preexcitation before ablation (n = 16; 47%), we found that the PR interval after ablation was significantly longer only in those without recurrence (162 ± 21 ms vs 134 ± 21 ms; P = .042). None of the other analyzed electrocardiographic parameters, including PR, QRS duration, and preexcitation, had prognostic impact. Conclusion: Acute success of complete ablation of atriofascicular pathways is associated with excellent long-term success (87%). Mere modification of conduction properties of atriofascicular fibers or ablation at the sites of mechanical block are less promising end points of ablation with high recurrence rates. Technical innovations during decades may not further improve long-term outcome in these patients.

Contact force–controlled zero-fluoroscopy catheter ablation of right-sided and left atrial arrhythmia substrates

2012-01-04

Background: Conventional catheter ablation of cardiac arrhythmias is associated with radiation risks for patients and laboratory personnel. However, nonfluoroscopic catheter guidance may increase the risk for inadvertent cardiac injury. A novel radiofrequency ablation catheter capable of real-time tissue-tip contact force measurements may compensate for nonfluoroscopic safety issues. Objective: To investigate the feasibility of contact force–controlled zero-fluoroscopy catheter ablation. Methods: In 30 patients (including 12 pediatric patients), zero-fluoroscopy catheter ablation of right-sided (right atrium, n = 20; right ventricle, n = 2) and left atrial (n = 8) arrhythmias was attempted. Inclusion criteria were symptomatic suspected atrioventricular nodal reentrant tachycardia, atrioventricular reentrant tachycardia, focal right atrial and ventricular arrhythmias, and lone atrial fibrillation. A novel irrigated-tip catheter with an integrated contact force sensor was used for nonfluoroscopic 3-dimensional electroanatomical mapping and radiofrequency ablation. Transseptal access was gained under transesophageal guidance for ablation of left-sided arrhythmias. Results: Procedural success without fluoroscopy was achieved in 29 of the 30 patients (97%). In 1 patient, endocardial nonfluoroscopic ablation failed because of an epicardial accessory pathway within a coronary sinus aneurysm. Mean total contact force and amplitude of force undulations were kept below 50 g during mapping and below 40 g during ablation to prevent contact force peaks (>100 g). Apart from a transient second-degree type I atrioventricular block, no complications occurred. The mean procedure time was 2.8 ± 0.9 hours. There were no arrhythmia recurrences during a mean follow-up of 6.2 ± 4.2 months. Conclusion: Contact force–controlled zero-fluoroscopy catheter ablation is generally feasible in right-sided and left atrial cardiac arrhythmias.

Radiation exposure: A silent complication of catheter ablation procedures

Mahmoud Houmsse, Emile G. Daoud — 2012-01-30

An underappreciated “silent complication” of catheter ablation procedures is radiation exposure. X-ray exposure results in acute complications related to dose- and time-dependent exposure as well as a cumulative, lifetime risk to not only the patient but also the operator and electrophysiology staff. These risks include acute and subacute dermatologic injury, musculoskeletal injury, cataracts, malignancy, and genetic defects. These risks are heightened for lengthy and multiple ablation procedures (eg, atrial fibrillation) and for vulnerable patients such as pediatric, obese, and pregnant patients.

Unpredictable battery depletion of St Jude Atlas II and Atlas+ II HF implantable cardioverter-defibrillators

2011-12-14

Background: Predictable progression to battery depletion is necessary for device management in patients with pacemakers or implantable cardioverter-defibrillators, particularly in patients who either are pacemaker dependent or have required implantable cardioverter-defibrillator therapies. Objective: To determine the incidence and characteristics of unexpected battery depletion in patients implanted with a cardiac resynchronization therapy – defibrillator (CRT-D) device. Methods: All patients with a St Jude Atlas+ HF or Atlas II HF CRT-D device implanted between 2004 and 2007 at the Massachusetts General Hospital and the Nashville VA Medical Center (Vanderbilt University) were studied. All patients with early generator depletion (transition of generator voltage above specified elective replacement indicator [ERI] to end of life [EOL] in less than 90 days) were evaluated further. Results: Eight cases (mean age 69.6 ± 9 years) with abrupt battery depletion were identified among 191 patients (4.2%) implanted with a St Jude Atlas CRT-D device. The longevity of 8 premature depletion devices was 46.4 ± 10 months (median 45 months). The battery voltage in these 8 devices decreased from a mean of 2.48 ± 0.03 V (above ERI) to 2.3 ± 0.08 V (below ERI) over 33.3 ± 23 days (range 1–59 days; median 38.5 days). One device reached EOL status within 1 day of having battery voltage above ERI and another device within 12 days. Conclusion: The incidence of abrupt battery depletion was 4.2% in patients implanted with a St Jude Atlas CRT-D device. No common mechanism has been identified for this failure. Close monitoring of battery voltage and timely generator replacement are required in patients with these devices.

Expecting the unpredictable

Beat Schaer, Christian Sticherling — 2012-01-05

The implantable cardioverter-defibrillator (ICD) is the cornerstone for the prevention of sudden cardiac death in high-risk patients. This has been proven time and again in numerous randomized trials and observational studies conducted over the last 20 years. However, its efficacy depends heavily on the predictability of device longevity and integrity. Impaired longevity confers risks to the patient associated with more frequent reoperations (infection, lead damage, etc). In addition, cost-effectiveness calculations are perturbed by significant differences between projected and observed device longevities. Impaired integrity might put the patient at risk for malignant arrhythmias that are not detected, not treated, or neither detected nor treated or at a risk of sudden deterioration of heart failure or syncope due to pacing failure.

Percutaneous extraction of stented device leads

2011-12-19

Background: There are limited published data regarding the percutaneous extraction of device leads jailed by a venous stent. Objective: In this study we assessed the feasibility and safety of percutaneous extraction of stented device leads. Methods: We reviewed our experience percutaneously extracting 7 chronically implanted device leads jailed to the wall of the left innominate and/or subclavian veins by a previously placed stent. Results: All leads were successfully extracted by using a percutaneous approach. Both pacing leads and defibrillator leads were extracted. The oldest pacing lead extracted was 14 years old. The oldest defibrillator lead extracted was 6 years old. Three of the leads were extracted with simple manual traction alone. The 4 remaining leads required a more complex, femoral extraction approach for successful removal. Conclusion: In our experience extracting 7 stented device leads, complete percutaneous removal was feasible 100% of the time using a combination of simple manual traction and a femoral approach. No major complications were associated with the extraction procedures.

Incidence and predictors of short- and long-term complications in pacemaker therapy: The FOLLOWPACE study

2011-12-19

Background: Today quantitative information about the type of complications and their incidence during long-term pacemaker (PM) follow-up is scarce. Objective: To assess the incidence and determinants of short- and long-term complications after first pacemaker implantation for bradycardia. Methods: A prospective multicenter cohort study (the FOLLOWPACE study) was conducted among 1517 patients receiving a PM between January 2003 and November 2007. The independent association of patient and implantation-procedure characteristics with the incidence of PM complications was analyzed using multivariable Cox regression analysis. Results: A total of 1517 patients in 23 Dutch PM centers were followed for a mean of 5.8 years (SD 1.1), resulting in 8797 patient-years. Within 2 months, 188 (12.4%) patients developed PM complications. Male gender, age at implantation, body mass index, a history of cerebrovascular accident, congestive heart failure, use of anticoagulant drugs, and passive atrial lead fixation were independent predictors for complications within 2 months, yielding a C-index of 0.62 (95% confidence interval 0.57–0.66). Annual hospital implanting volume did not additionally contribute to the prediction of short-term complications. Thereafter, 140 (9.2%) patients experienced complications, mostly lead-related complications (n = 84). Independent predictors for long-term complications were age, body mass index, hypertension, and a dual-chamber device, yielding a C-index of 0.62 (95% confidence interval 0.57–0.67). The occurrence of a short-term PM complication was not predictive of future PM complications. Conclusions: Complication incidence in modern pacing therapy is still substantial. Most complications occur early after PM implantation. Although various patient- and procedure-related characteristics are independent predictors for early and late complications, their ability to identify the patient at high risk is rather poor. This relatively high incidence of PM complications and their poor prediction underscores the usefulness of current guidelines for regular follow-up of patients with PM.

Potential mechanisms underlying the effect of gender on response to cardiac resynchronization therapy: Insights from the SMART-AV multicenter trial

2011-12-19

Background: Recent studies demonstrate that women may respond more favorably to cardiac resynchronization therapy (CRT) than do men. The mechanisms remain unclear. Objectives: To describe the effects of gender on response to CRT and to explore potential mechanisms behind these differences. Methods: Data for 846 patients from the SMART-AV trial were used to evaluate the mechanisms behind the effects of gender on CRT response. Atrioventricular optimization (AVO) was performed via SmartDelay or echocardiography. Baseline and 6-month left ventricular end systolic volume index (LVESVi) were fitted to a linear regression model with gender predicting change in LVESVi and adjusted for baseline covariates significantly differing by gender. The interaction variable for AVO and gender was also assessed for its effect on change in LVESVi. Results: Baseline variables, including age, body mass index, left ventricular ejection fraction, QRS width, and severity of heart failure symptoms, were comparable between men and women. Women had a higher incidence of left bundle branch block conduction and nonischemic cardiomyopathy and exhibited greater reductions in LVESVi even after adjustment for these differences (13.4 mL/m2 vs 8.5 mL/m2; P = .002). In addition, women had greater percentages of biventricular pacing and appeared to derive greater reductions in left ventricular volume with AVO than did men. Conclusions: Women demonstrated greater reductions in LVESVi with CRT than did men. These observations are not explained by differences in baseline characteristics. Greater degrees of biventricular pacing and enhanced response to AVO in women may partly explain the reason for the gender effect on CRT response.

Riata implantable cardioverter-defibrillator lead failure: Analysis of explanted leads with a unique insulation defect

Robert G. Hauser, Deepa McGriff, Linda Kallinen Retel — 2011-12-30

Background: The Riata family of implantable cardioverter-defibrillator leads (St Jude Medical, Sylmar, CA) appears prone to a unique failure mechanism whereby the conductor cables wear through the silicone insulation from inside-out and are seen outside the lead body (externalized conductors). Objective: To assess the extent of Riata lead damage associated with inside-out insulation defects and their clinical consequences. Methods: In September 2011, we searched the U.S. Food and Drug Administration's Manufacturers and User Defined Experience medical device database for reports describing Riata lead failures that had been analyzed by the manufacturer. Results: The Manufacturers and User Defined Experience search identified 105 leads that had inside-out insulation defects. Eight-French single-coil Riata leads accounted for a higher-than-expected proportion (25.7%) of the leads with this defect. A total of 226 insulation defects were found in the 105 leads (2.2 defects per lead), including 143 inside-out defects (1.4 defects per lead). The most common location of insulation defects was distal to the proximal coil (n = 108). Twenty-eight leads (26.7%) had inside-out insulation defects underneath the shocking coils. Of 43 leads whose cables were assessed for the integrity of the ethylene-tetrafluoroethylene cable coating, 22 (51.2%) were found to be abraded, exposing the conductor surfaces. On X-ray radiography or fluoroscopy, 7 leads were found to have externalized cables; 2 of these leads had no electrical abnormalities, while 4 exhibited noise or increased impedance. Inappropriate shocks were experienced by 31 of the 105 patients (29.5%). Conclusion: Riata leads that have inside-out insulation defects often have multiple defects, including additional inside-out abrasions along the body of the lead and beneath the shocking coils. Eight-French single-coil Riata models may be more prone to externalized cables than are dual-coil and 7-F designs. Externalized cables are but one manifestation of interior insulation damage. Our findings question the durability of the ethylene-tetrafluoroethylene cable coating on exposed cables.

The Riata story—Where are we now?

Charles A. Henrikson — 2012-01-16

One hundred fifty-seven thousand Riata leads were placed in patients in the United States, and it took over 8 years from the time of first implantation to recognize “inside-out abrasion” as a significant problem with the lead. This recently described problem appears to be unique, with the conductors eroding out through the insulation in an “inside-out” manner. The initial reports of this were found after patients presented with electrical abnormalities in the lead and were found to have externalized conductors. Now that the problem is recognized, further analysis has found the precursor lesion to this problem, namely, areas of insulation worn in an inside-out fashion without full externalization of the conductors. While this is related to electrical abnormalities in the lead in some cases, a finding of abnormal function of the lead is far from universal, and so the management of these patients is a developing challenge.

Identification of high-risk syncope related to ventricular fibrillation in patients with Brugada syndrome

2011-11-28

Background: Syncope in patients with Brugada syndrome is usually associated with ventricular tachyarrhythmia, but some episodes of syncope can be related to autonomic disorders. Objective: The purpose of this study was to investigate the characteristics of syncope to differentiate high-risk syncope episodes from low-risk events in patients with Brugada syndrome. Methods: We studied 84 patients with type 1 electrocardiogram and syncope. Patients were divided into 2 groups: patients with prodrome (prodromal group; n = 41) and patients without prodrome (nonprodromal group; n = 43). Results: Ventricular fibrillation (VF) was documented at index event in 19 patients: 4 patients (21%) with documented VF experienced a prodrome prior to the onset of VF, whereas 15 patients (79%) did not have symptoms prior to documented VF (P <.01). Twenty-seven patients in the prodromal group and 7 patients in the nonprodromal group were considered to have syncope related to autonomic dysfunction. Syncope in other patients was defined as unexplained syncope. During the follow-up period (48 ± 48 months), recurrent syncope due to VF occurred in 13 patients among patients with only unexplained syncope and was more frequent in the nonprodromal group (n = 10) than in the prodromal group (n = 3; P = .044). In multivariate analysis, blurred vision (hazard ratio [HR] 0.20) and abnormal respiration (HR 2.18) and fragmented QRS (HR 2.39) were independently associated with the occurrence of VF. Conclusion: Syncope with prodrome, especially blurred vision, suggests a benign etiology of syncope in patients with Brugada syndrome.

A novel rare variant in SCN1Bb linked to Brugada syndrome and SIDS by combined modulation of Nav1.5 and Kv4.3 channel currents

2011-12-08

Background: Cardiac sodium channel β-subunit mutations have been associated with several inherited cardiac arrhythmia syndromes. Objective: To identify and characterize variations in SCN1Bb associated with Brugada syndrome (BrS) and sudden infant death syndrome (SIDS). Methods: All known exons and intron borders of the BrS-susceptibility genes were amplified and sequenced in both directions. Wild type (WT) and mutant genes were expressed in TSA201 cells and studied using co-immunoprecipitation and whole-cell patch-clamp techniques. Results: Patient 1 was a 44-year-old man with an ajmaline-induced type 1 ST-segment elevation in V1 and V2 supporting the diagnosis of BrS. Patient 2 was a 62-year-old woman displaying a coved-type BrS electrocardiogram who developed cardiac arrest during fever. Patient 3 was a 4-month-old female SIDS case. A R214Q variant was detected in exon 3A of SCN1Bb (Nav1B) in all three probands, but not in any other gene previously associated with BrS or SIDS. R214Q was identified in 4 of 807 ethnically-matched healthy controls (0.50%). Co-expression of SCN5A/WT + SCN1Bb/R214Q resulted in peak sodium channel current (INa) 56.5% smaller compared to SCN5A/WT + SCN1Bb/WT (n = 11–12, P<0.05). Co-expression of KCND3/WT + SCN1Bb/R214Q induced a Kv4.3 current (transient outward potassium current, Ito) 70.6% greater compared with KCND3/WT + SCN1Bb/WT (n = 10–11, P<0.01). Co-immunoprecipitation indicated structural association between Navβ1B and Nav1.5 and Kv4.3. Conclusion: Our results suggest that R214Q variation in SCN1Bb is a functional polymorphism that may serve as a modifier of the substrate responsible for BrS or SIDS phenotypes via a combined loss of function of sodium channel current and gain of function of transient outward potassium current.

SCN1Bb R214Q found in 3 patients: 1 with Brugada syndrome and 2 with lone atrial fibrillation

2011-12-08

Background: SCN1Bb encodes the β-subunit of the sodium channel. A mutation in SCN1Bb R214Q has recently been shown both to increase the Kv4.3 current and to decrease the sodium current. The variant was suggested to increase the susceptibility to Brugada syndrome (BrS). Objective: To sequence a population of BrS and early-onset lone atrial fibrillation (AF) patients for the R214Q mutation in the SCN1Bb gene. Methods: The coding sequence and splice junctions of SCN1Bb were bidirectionally sequenced by using Big Dye chemistry in 192 early-onset lone AF patients and 22 BrS patients. Results: Three probands carrying the R214Q variant were identified. No mutations were identified in genes previously associated with BrS or AF in these patients. Case 1 also had the onset of persistent lone AF at the age of 39 years. Case 2 was a lone AF case with onset at the age of 39 years and paroxysmal lone AF. Case 3 was a BrS patient with a type 1 electrocardiogram and onset of disease at the age of 54 years. Both lone AF patients had electrocardiograms that raised the suspicion of BrS, but intravenous flecainide testing was, in both cases, negative. R214Q was not present in the control group (n = 216) and has not previously been reported in conjunction to AF. Conclusion: Three patients of 192 young lone AF and 22 BrS patients carried the nonsynonymous R214Q mutations in SCN1Bb, thereby indicating that this variant increases the susceptibility to both BrS and AF.

SCN1Bb, atrial fibrillation, and Brugada syndrome: Just another brick in the wall …

Vincent Probst, Jean-Baptiste Gourraud, Hervé Le Marec — 2012-01-03

“Brugada syndrome (BrS) is an inherited cardiac arrhythmia characterized by an ST segment elevation in the right precordial leads and an associated risk of sudden cardiac death due to ventricular fibrillation.”

Drug-induced QT-interval shortening following antiepileptic treatment with oral rufinamide

2012-01-13

Background: The arrhythmogenic potential of short QT intervals has recently been highlighted in patients with a short QT syndrome. Drug-induced QT-interval prolongation is a known risk factor for ventricular tachyarrhythmias. However, reports on drug-induced QT-interval shortening are rare and proarrhythmic effects remain unclear. Objective: Recently, rufinamide, a new antiepileptic drug for the add-on treatment of Lennox-Gastaut syndrome, was approved in the European Union and the United States. Initial trials showed drug-induced QT-interval shortening. The aim of our study was to evaluate the effects of rufinamide on QT intervals in patients with difficult-to-treat epilepsies. Methods: Nineteen consecutive patients with Lennox-Gastaut syndrome and other epilepsy syndromes were included (n = 12 men; mean age 41 ± 12 years). QRS, QT, and Tpeak-Tend intervals were analyzed before and during rufinamide treatment. Results: The mean QT interval shortened significantly following rufinamide administration (QT interval 349 ± 23 ms vs 327 ± 17 ms; corrected QT interval 402 ± 22 ms vs 382 ± 16 ms; P = .002). Tpeak-Tend intervals were 79 ± 17 ms before and 70 ± 20 ms on treatment (P = .07). The mean reduction of the corrected QT interval was 20 ± 18 ms. During follow-up (3.04 ± 1.09 years), no adverse events including symptomatic cardiac arrhythmias or sudden cardiac deaths were observed. Conclusion: QTc-interval shortening following oral rufinamide administration in a small patient group was not associated with significant clinical adverse effects. These observations nothwithstanding, the ability of rufinamide to significantly shorten the QT interval portends a potential arrhythmogenic risk that may best be guarded against by periodic electrocardiographic recordings.

Electrocardiographic characteristics of patients with false tendon: Possible association of false tendon with J waves

2012-01-03

Background: The false tendons (FTs) are fibromuscular bands that transverse the left ventricular cavity and often contain conduction tissue, suggesting that FTs may contribute to the occurrence of ventricular arrhythmias. The presence of J waves is associated with vulnerability to ventricular arrhythmias; however, the mechanisms underlying the manifestation of J waves remain to be elucidated. Objective: To investigate the electrocardiographic characteristics, including the presence of J waves, in patients with FTs. Methods: We studied 44 patients with distinct FTs detected by echocardiography (FT group) and 88 age- and sex-matched healthy subjects without FTs (control group). The PQ, QRS, JT, QT, corrected JT, and corrected QT intervals were automatically measured on surface 12-lead electrocardiograms, and the presence or absence of J waves was also determined. J waves were defined as terminal QRS notching or slurring. FTs were classified according to their points of attachment as type 1 (longitudinal, 52%), type 2 (diagonal, 25%), type 3 (transverse, 16%), and type 4 (weblike, 7%). Results: QRS and corrected QT intervals were significantly longer in the FT group than in the control group (P <.005 and P <.05, respectively). The incidence of J waves was significantly higher in the FT group (64%) than in the control group (19%) (P <.0001). J waves were more prevalent in type 1 (78%) and type 2 (73%) than in type 3 (14%) and 4 FTs (33%) (P <0.05) and in patients with thick FTs (≥2 mm) than with thinner FTs (<2 mm) (71% vs 33%; P <.05). The J-wave location differed according to the FT type. Conclusions: Our results suggest that FTs may carry a certain role to the genesis of J waves.

Networked multielectrode left ventricular pacing lead for avoidance of phrenic nerve stimulation in a canine model

2011-12-02

Background: In cardiac resynchronization therapy, left ventricular stimulation may lead to concomitant phrenic nerve stimulation (PNS). Objective: To evaluate a new networked multielectrode lead with 16 electrode segments (SEGs) configured into groups of 4, forming a virtual band (VBAND) around the lead. Each electrode is individually programmable using an embedded integrated circuit. Methods: In 8 anesthetized dogs, the lead was positioned in a left ventricular coronary vein. The voltage thresholds for cardiac stimulation and PNS were measured for different electrode configurations, including “VBAND-VBAND” (∼conventional bipolar pacing), “SEG-VBAND”, and “SEG-SEG” (anode and cathode within the same VBAND). The measurements were performed (1) with closed chest and (2) after opening the chest and repositioning the phrenic nerve to above the lead, simulating a worst-case scenario. Results: Compared with the conventional VBAND-VBAND stimulation, the SEG-SEG stimulation increased the PNS threshold and raised the difference between phrenic and cardiac thresholds from 6.2 ± 2.3 to 9.5 ±0.3 V in the closed chest condition and from 1.4 ± 1.6 to 9.0 ± 1.0 V in the worst-case scenario (both P < .001). Both SEG-VBAND and SEG-SEG stimulations reduced the cardiac threshold and increased pacing impedance, thus reducing the required cardiac pacing power by 77%–80% (P <.001 and P <.01 for closed and open chest, respectively). Conclusion: This novel multielectrode pacing lead achieves low cardiac and high extracardiac stimulation thresholds during left ventricular pacing in a canine model. The virtual elimination of PNS may facilitate and improve the application of cardiac resynchronization therapy.

The peak-to-end of the T wave in the limb ECG leads reflects total spatial rather than transmural dispersion of ventricular repolarization in an anthopleurin-A model of prolonged QT interval

2011-11-28

Background: Previous studies have showed that the interval between the peak and the end of the T wave (Tp-e) is a marker of transmural dispersion of ventricular repolarization. Objective: We studied the relationship between (a) the Tp-e on local pseudo transmural electrograms (pseudo transmural Tp-e) or limb leads of body surface electrocardiogram (surface Tp-e) and (b) the intracardiac left ventricular (LV) repolarization during a drug-induced QT-interval prolongation. Methods: Using open-chested canine intact hearts treated by anthopleurin-A, transmural LV electrograms were recorded via needle electrodes placed in the basoanterior, midanterior, apicoanterior, basolateral, midlateral, and apicolateral LV wall. Recovery time (RT) was calculated as an index of local repolarization at each transmural unipolar electrode. Results: This model showed slower heart rate–dependent heterogeneous distribution of ventricular repolarization both along the basal to apical axis and along the transmural axis. RT was longer at the LV apex than at the base and longer in the lateral than in the anterior wall during the slower heart rate. A high correlation was found between surface Tp-e and total LV dispersion. In contrast, pseudo transmural Tp-e correlated with transmural RT dispersion. The shortest RT in the heart roughly corresponded to the peak, as did the longest RT with the end of the T wave on the surface electrocardiogram. Conclusion: During drug-induced QT-interval prolongation with a large apicobasal and anterolateral dispersion of ventricular repolarization, the Tp-e in the limb leads expresses spatial (total) distribution of repolarization in the whole left ventricle.

Interactions between atrial electrical remodeling and autonomic remodeling: How to break the vicious cycle

2012-01-04

Background: The mechanism(s) underlying the maintenance of atrial fibrillation (AF) during the first few hours after AF was initiated remains poorly understood. Objective: To investigate the roles of the intrinsic cardiac autonomic nervous system in the maintenance of AF at the early stage. Methods: In 10 anesthetized dogs, we attached multielectrode catheters on atria and pulmonary veins. Microelectrodes inserted into the anterior right ganglionated plexi recorded neural activity. At baseline, programmed stimulation determined the effective refractory period (ERP) and window of vulnerability (WOV), a measure of AF inducibility. For the next 6 hours, AF was simulated by rapid atrial pacing (RAP) and the same parameters were measured hourly during sinus rhythm. A circular catheter was positioned in the superior vena cava for high-frequency stimulation (20 Hz) of the adjacent vagal preganglionics. During 4−6 hours of RAP, we delivered low-level vagal stimulation in the superior vena cava (LL-SVCS), 50% below that which induced slowing of the sinus rate. Results: During the 6-hour RAP, there was a progressive decrease in the ERP and an increase in ERP dispersion, WOV, and neural activity. With LL-SVCS during 4−6-hour RAP, ERP, WOV, and neural activity returned toward baseline levels (all P <.05, compared with the third-hour RAP values). Conclusions: RAP not only induces atrial electrical remodeling but also promotes autonomic remodeling. These 2 remodeling processes may form a vicious cycle and each may perpetuate the other. These findings may help to explain how AF maintains itself in its very early stage. LL-SVCS both reversed remodeling processes and can potentially break the vicious cycle of “AF begets AF” in the first few hours of AF.

Disease modification by autonomic nerve stimulation

Seil Oh — 2012-01-30

One of the arrhythmogenic mechanisms in the pathophysiology of atrial fibrillation (AF) is autonomic influence. The activation of cardiac autonomic nerves results in electrophysiological changes, causing shortening of the atrial effective refractory period and action potential duration, and spatial heterogeneity of refractoriness. Such conditions favor the initiation and maintenance of atrial tachyarrhythmias such as AF. Coumel et al reported that vagus nerve might be associated with paroxysmal AF. Studies using heart rate variability analysis have confirmed that paroxysmal AF occurrence is associated with a primary increase in adrenergic tone followed by a marked modulation toward vagal predominance. Recently, direct recording of intrinsic cardiac nerve activities in ambulatory animals revealed that the nerve activities are invariable triggers of paroxysmal AF.

BIN1 is reduced and Cav1.2 trafficking is impaired in human failing cardiomyocytes

2011-12-05

Background: Heart failure is a growing epidemic, and a typical aspect of heart failure pathophysiology is altered calcium transients. Normal cardiac calcium transients are initiated by Cav1.2 channels at cardiac T tubules. Bridging integrator 1 (BIN1) is a membrane scaffolding protein that causes Cav1.2 to traffic to T tubules in healthy hearts. The mechanisms of Cav1.2 trafficking in heart failure are not known. Objective: To study BIN1 expression and its effect on Cav1.2 trafficking in failing hearts. Methods: Intact myocardium and freshly isolated cardiomyocytes from nonfailing and end-stage failing human hearts were used to study BIN1 expression and Cav1.2 localization. To confirm Cav1.2 surface expression dependence on BIN1, patch-clamp recordings were performed of Cav1.2 current in cell lines with and without trafficking-competent BIN1. Also, in adult mouse cardiomyocytes, surface Cav1.2 and calcium transients were studied after small hairpin RNA–mediated knockdown of BIN1. For a functional readout in intact heart, calcium transients and cardiac contractility were analyzed in a zebrafish model with morpholino-mediated knockdown of BIN1. Results: BIN1 expression is significantly decreased in failing cardiomyocytes at both mRNA (30% down) and protein (36% down) levels. Peripheral Cav1.2 is reduced to 42% by imaging, and a biochemical T-tubule fraction of Cav1.2 is reduced to 68%. The total calcium current is reduced to 41% in a cell line expressing a nontrafficking BIN1 mutant. In mouse cardiomyocytes, BIN1 knockdown decreases surface Cav1.2 and impairs calcium transients. In zebrafish hearts, BIN1 knockdown causes a 75% reduction in calcium transients and severe ventricular contractile dysfunction. Conclusions: The data indicate that BIN1 is significantly reduced in human heart failure, and this reduction impairs Cav1.2 trafficking, calcium transients, and contractility.

Impairment of trafficking by downregulation of an anchor protein: Novel insights into additional mechanisms responsible for heart failure

Marc A. Vos, Karin R. Sipido — 2012-02-02

Adaptations of the heart to disease are often referred to as cardiac remodeling. On the ventricular level, this remodeling, among others, can be noticed in changes in the structure and in altered electrical and contractile function. These alterations can be sufficient to overcome the pathological stimulus (compensated remodeling); in other moments, they are inadequate and the heart function starts to deteriorate (decompensation), leading to heart failure. A hallmark of ventricular remodeling is the altered expression and/or function of the major protein components of the electrical to mechanical coupling. This includes upregulation and downregulation of ion channels responsible for the generation of the cardiac action potential and the proteins involved in subsequent calcium regulation and contraction. In contrast to a number of mutations that result in a gain or loss of function of individual macromolecules, the intrinsic function is often preserved, but the overall protein expression level is altered. Alternatively, protein function is modulated, for example, by phosphorylation, or changes are made in modulating proteins in macrocomplexes, as, for example, accessory subunits of the voltage-activated channels. The signals involved in these remodeling processes of altered expression, translation, and posttranslational modifications are intensively investigated and pivotal cellular and nuclear proteins such as mitogen activated protein kinase (MAPK), calcium/calmodulin-dependent protein kinase together with histone deacetylase (CAMKII-HDAC) and calcineurin-NFAT (nuclear factor of activated T-cells) have been identified.

Estradiol promotes sudden cardiac death in transgenic long QT type 2 rabbits while progesterone is protective

2012-01-13

Background: Postpubertal women with inherited long QT syndrome type 2 (LQT2) are at increased risk for polymorphic ventricular tachycardia (pVT) and sudden cardiac death (SCD), particularly during the postpartum period. Objective: To investigate whether sex hormones directly modulate the arrhythmogenic risk in LQTS. Methods: Prepubertal ovariectomized transgenic LQT2 rabbits were treated with estradiol (EST), progesterone (PROG), dihydrotestosterone (DHT), or placebo (OVX). Results: During 8 weeks of treatment, major cardiac events—spontaneous pVT or SCD—occurred in 5 of the 7 EST rabbits and in 2 of the 9 OVX rabbits (P <.05); in contrast, no events occurred in 9 PROG rabbits and 6 DHT rabbits (P <.01 vs PROG; P <.05 vs DHT). Moreover, EST increased the incidence of pVT (P <.05 vs OVX), while PROG reduced premature ventricular contractions, bigeminy, couplets, triplets, and pVT (P <.01 vs OVX; P <.001 vs EST). In vivo electrocardiographic monitoring, in vivo electrophysiological studies, and ex vivo optical mapping studies revealed that EST promoted SCD by steepening the QT/RR slope (P <.05), by prolonging cardiac refractoriness (P <.05), and by altering the spatial pattern of action potential duration dispersion. Isoproterenol-induced Ca2+ oscillations resulted in early afterdepolarizations in EST-treated hearts (4 of 4), while PROG prevented SCD by eliminating this early afterdepolarization formation in 4 of the 7 hearts (P = .058 vs EST; P <.05 vs OVX). Analyses of ion currents demonstrated that EST increased the density of ICa,L as compared with OVX (P <.05) while PROG decreased it (P <.05). Conclusion: This study reveals the proarrhythmic effect of EST and the antiarrhythmic effect of PROG in LQT2 in vivo, outlining a new potential antiarrhythmic therapy for LQTS.

Sex hormones and ventricular tachyarrhythmias in LQTS: New insights regarding antiarrhythmic therapy

Arthur J. Moss — 2012-01-20

Following the first publication of long QT syndrome (LQTS) involving several members of a family with QT prolongation, deafness, and lethal cardiac arrhythmias by Jervell and Lange-Nielsen in 1957, this arrhythmogenic disorder was recognized as a hereditary condition. Subsequent studies have shown that the most common form of LQTS is an autosomal dominant disorder without deafness but with variable penetrance and expressivity. Initial case reports showed a relative preponderance of women with LQTS. The location of the first genetic mutation associated with LQTS was identified by Keating et al in 1991, and presently mutations on 12 genes have been linked to LQTS. We and others have shown that the major risk factors for life-threatening cardiac events are the duration of the corrected QT (QTc) interval, especially values greater than 500 ms, and an episode of abrupt onset-offset syncope in the past few years. Recent mutational studies have shown that certain characteristics of the LQTS mutation including its biophysical function and its location in the channel protein influence the virulence of the genetic disorder.

Connexin43 and the regulation of intercalated disc function

Mario Delmar, Feng-Xia Liang — 2011-11-03

Gap junctions mediate the passage of ions and small molecules between cells. In the adult working cardiac ventricles, gap junctions are formed predominantly by the oligomerization of the 43-kDa protein Connexin43 (Cx43). It is generally accepted that gap junction–mediated intercellular communication is modulated by changes in the intracellular environment. The activity of various kinases, the concentration of protons or calcium, and the association of Cx43 with other intracellular components all converge to determine the filtering capabilities of intercellular channels. The most studied posttranslational modification of Cx43 is the phosphorylation of amino acids in its C-terminal domain (see, eg, References and ). Additional studies have shown that Cx43 is also a substrate for Nε-lysine acetylation. Changes in the ionic intracellular milieu can also, directly or indirectly, regulate the conductive state of Cx43. These modulatory mechanisms are likely to be activated in various pathophysiological states. Given the key role of gap junctions in action potential propagation, Cx43 regulation is a subject of intense research, and it is seen as an important pharmacological target for the treatment and/or prevention of cardiac arrhythmias.

Reversal of left bundle and His bundle potentials during wide complex tachycardia: What is the mechanism?

Apoor Patel, Steven M. Markowitz, Eran S. Zacks, Bruce B. Lerman — 2011-01-18

A 14-year-old male patient presented to our institution with a wide complex tachycardia. An echocardiogram showed an ejection fraction of 60%, moderate mitral and tricuspid regurgitation, mild aortic regurgitation, and moderate pulmonary hypertension. He had a history of 2 prior ablations at another institution. During his first procedure, he was found to have ventricular tachycardia with a right bundle branch block, left superior axis morphology at a cycle length of 375 ms. Cryoablation was performed along the mid-left ventricular septum, after which the patient developed a left posterior fascicular block pattern during sinus rhythm. The next day, the patient developed ventricular tachycardia with a right bundle branch block, right inferior axis morphology. Ablation was targeted in the region of the left anterior fascicle and rendered the tachycardia noninducible. After the procedure, the electrocardiogram demonstrated a left bundle branch block configuration. Several months later, the patient presented to our institution in a wide complex tachycardia with a left bundle branch block, left superior axis morphology. Electrocardiograms during sinus rhythm and tachycardia are shown (A and B). During electrophysiological study, baseline AH and HV intervals were 87 ms and 55 ms, respectively. The HV remained constant during incremental atrial pacing. Tachycardia was reproducibly induced with rapid atrial and ventricular pacing, and had a cycle length of 370 ms and an HV interval of 55 ms. Atrial activity was dissociated from the tachycardia. Adenosine 24 mg had no effect on tachycardia cycle length. Intracardiac tracings during sinus rhythm () and tachycardia () are shown.

Electrical storm due to managed ventricular pacing

Fadi Mansour, Paul Khairy — 2011-11-03

A 70-year-old man with a dual-chamber implantable cardioverter-defibrillator (ICD; Secura DR, Medtronic, Minneapolis, MN) presented with multiple shocks. The ICD was implanted 8 months earlier for primary prevention in the context of ischemic cardiomyopathy (ejection fraction 35%) and nonsustained ventricular tachycardia (VT). He had no known atrial tachyarrhythmia or conduction system disease and received no antiarrhythmic drug therapy. The ICD was programmed in the managed ventricular pacing (MVP; AAI–DDD) mode at a lower rate of 50 beats/min, with a monitoring zone at 150 beats/min, and a ventricular fibrillation zone (fast VT via ventricular fibrillation) set to 182–250 beats/min, with 2 antitachycardia pacing attempts followed by shocks.

Atrial flutter: Right, left, or both?

Nicolas Clementy, Bertrand Pierre, Laurent Fauchier, Dominique Babuty — 2010-12-27

A 66-year-old man with a history of surgical removal of a left atrial myxoma was admitted to our department for radiofrequency ablation of a symptomatic atrial flutter. Baseline ECG showed atrial flutter with variable atrioventricular conduction and narrow QRS complexes (). Atrial activity showed an aspect of intraatrial conduction delay. Echocardiography showed normal left ventricular function and no atrial dilation.

Erratum

2012-04-05

In the article, “Deubiquitylating enzyme USP2 counteracts Nedd4-2–mediated downregulation of KCNQ1 potassium channels,” by Katarzyna Krzystanek et al, that published in the March 2012 issue of HeartRhythm (2012; 9: 440–448) the academic degrees of Drs Krzystanek and Jespersen were inaccurate. The corrected degrees for all authors are listed below: Katarzyna Krzystanek PhD, *† Hanne Borger Rasmussen, PhD,* Morten Grunnet, PhD,*‡ Olivier Staub, PhD,§ Søren-Peter Olesen, MD, PhD,* Hugues Abriel, MD, PhD,† Thomas Jespersen, PhD, MD Sci*.

EP News: Basic and Translational

Peng-Sheng Chen — 2012-04-02

Patients with dilated cardiomyopathy are at high risk for ventricular arrhythmia and sudden cardiac death. According to the Heart Rhythm Society Consensus Statement on the State of Genetic Testing for the Channelopathies and Cardiomyopathies (Ackerman et al, HeartRhythm 2011;8:1308–1339), none of the >25 known disease-associated genes has been shown to account for ≥5% of this disease. A recent article by Herman et al (N Engl J Med 2012;366:619, PMID 22335739) is likely to change that statement. The authors analyzed TTN (the gene encoding the sarcomere protein titin) in 312 subjects with dilated cardiomyopathy, 231 subjects with hypertrophic cardiomyopathy, and 249 controls. They were able to identify 72 unique mutations that altered full-length titin. The frequency of TTN mutations was significantly higher among subjects with dilated cardiomyopathy (27%) than among subjects with hypertrophic cardiomyopathy (1%) or controls (3%). TTN mutations cosegregated with dilated cardiomyopathy in families with high (>95%) observed penetrance after the age of 40 years. Mutations associated with dilated cardiomyopathy were overrepresented in the titin A-band but were absent from the Z-disk and M-band regions of titin. More than half of the patients in the study have an implantable cardioverter-defibrillator. Overall, the rates of cardiac outcomes were similar in subjects with and those without TTN mutations, but adverse events occurred earlier in male mutation carriers than in female carriers. The authors suggest that truncated titin proteins found in subjects with dilated cardiomyopathy may be integrated into the sarcomere and cause dilated cardiomyopathy by means of a dominant negative mechanism. The authors conclude that TTN truncating mutations are a common cause of dilated cardiomyopathy, occurring in approximately 25% of familial cases of idiopathic dilated cardiomyopathy and in 18% of sporadic cases. Incorporation of sequencing approaches that detect TTN truncations into genetic testing for dilated cardiomyopathy should substantially increase test sensitivity, thereby allowing earlier diagnosis and therapeutic intervention for many patients with dilated cardiomyopathy.

EP News: Clinical

N.A. Mark Estes — 2012-03-29

Hohnloser et al (Circulation 2012;125:669–676, PMID 22215856) evaluated the rates of myocardial infarction (MI), unstable angina, cardiac arrest, and cardiac death and the prespecified net clinical benefit and treatment effects of dabigatran (D) vs warfarin (W) in the RE-LY (Randomized Evaluation of Long-Term Anticoagulation Therapy) study. MI occurred at annual rates of 0.82% and 0.81% with D 110 or 150 mg bid compared with 0.64% with W (hazard ratio [HR] 1.29, P = .09 for D 110 mg; HR 1.27, P = .12 for D 150 mg). Annual rates of a composite of MI, unstable angina, cardiac arrest, and cardiac death were 3.16% per year with D 110 mg, 3.33% per year with D 150 mg, and 3.41% per year with W (HR 0.93, P = .28 for D 110 mg; HR 0.98, P = .77 for D 150 mg). Events prespecified as net clinical benefit occurred at a rate of 7.34% per year with D 110 mg, 7.11% per year with D 150 mg, and 7.91% per year with W (HR 0.92, P = .09 for D 110 mg; HR 0.90, P = .02 for D 150 mg). The authors conclude that there was a nonsignificant increase in MI with D compared with W, but other myocardial ischemic events were not increased.

Early Repolarization ECG Pattern in Patients with ARVC: Normal Variant?

2012-03-14

We read with interest the study entitled “Clinical phenotype and diagnosis of arrhythmogenic right ventricular cardiomyopathy in pediatric patients carrying desmosomal gene mutations” by Bauce et al in the November 2011 issue of HeartRhythm. The ECG displayed in their Figure 1 shows early repolarization (ER) and “J waves” in the inferior leads, but whether this ECG should be considered normal, as the authors remark, is arguable. Moreover, “J waves” are not specifically pointed out as one of the “ECG [electrocardiogram] features” in their Table 2, although an “RV conduction delay” is mentioned.

Clinical phenotype and diagnosis of arrhythmogenic right ventricular cardiomyopathy in pediatric patients carrying desmosomal gene mutations

Barbara Bauce, Domenico Corrado, Gaetano Thiene — 2012-03-14

We thank Dr. Rodríguez-Mañero et al for their interest in our article. They argue that the ECG of our Figure 1 should not be considered normal because of the presence of signs of early repolarization (ER) in the inferior leads. ER has traditionally been regarded as an idiopathic and benign ECG phenomenon, with an estimated prevalence in healthy young individuals of 1% to 2%, and a clear male preponderance. The ER pattern is the rule rather than the exception among highly trained athletes, in whom the pattern is observed in 50% to 80% of resting ECGs. The ER repolarization ECG shows elevation of the QRS–ST junction (J point) of at least 0.1 mV from baseline, associated with notching or slurring of the terminal QRS complex that may vary in degree, morphology, and location. ER recently has gained renewed interest because of its possible association with idiopathic ventricular fibrillation and thus is considered a potential marker of arrhythmic risk. It has been advanced that a malignant variant of ER may share electrogenetic and arrhythmogenic mechanisms with Brugada syndrome, both conditions being included among the so-called “J-wave syndromes.” Of note, in patients with Brugada syndrome, the presence of inferior–lateral slurring of terminal QRS (inferolateral “J waves”) has been demonstrated to be associated with a more severe phenotype.

Statins and Postoperative Atrial Fibrillation: A Long Way Ahead

2012-03-26

Bhave et al examined the effect of statin use and the incidence of postoperative atrial fibrillation (AF) in patients undergoing major noncardiac surgery. They concluded that these medications are associated with markedly reduced odds of developing clinically significant AF. However, several limitations preclude this conclusion. First, the authors used length of stay as a classification of high-risk surgery, which is not recognized by the current guidelines as a criterion for procedure stratification and was not validated in this or previous studies. Second, the time window considered for “statin use” was too narrow, excluding those patients who had used statins until the day before the procedure. Furthermore, drug discontinuation should have been included in the analysis because, as the authors state, it is a well-known risk factor for cardiovascular complications. To reduce the possibility of false-positive cases, the authors excluded intravenous beta-blocker from the outcome variable as well as digoxin, amiodarone, calcium channel blockers, and cardioversion in separate analyses. However, this was done in a bivariate fashion and not as multivariate. It would have been useful if the authors could have provided a table with the characteristics of the perioperative matched cohort after multivariate analyses of the whole population. It also is of concern that the costs and the length of stay were not different between the two groups, although it is well known, as the authors says in the Introduction, that AF is associated with higher morbidity and health care costs. This could represent a residual unmeasured bias not identified in the study that could have been considered in the analyses. To overcome this scenario, it is recommended that the authors evaluate a tracer outcome that is certainly not influenced by statin use, which was already done in previous databank studies. If there are no differences in the group results, the possibility of unrecognized confounding is much lower.

Statin use and postoperative atrial fibrillation after major noncardiac surgery

Prashant D. Bhave, Andrew Auerbach — 2012-03-26

We thank Carmo et al for their interest in our work. Although we agree that we lacked data on prehospital use of statins, it seems unlikely that these drugs were started only in the hospital or afterward. We did define perioperative statin administration strictly because we believed that statins that were initiated later during the hospital stay likely were started in response to a clinical event, such as myocardial infarction.

Postrepolarization Refractoriness in Acute Ischemia and After Antiarrhythmic Drug Administration

Sandeep V. Pandit, Sami F. Noujaim, José Jalife — 2012-03-19

We read the review article by Coronel et al regarding the concept of postrepolarization refractoriness in acute ischemia. They began their second paragraph citing our work as follows: Thus action potential duration is widely used as a measure of refractory period, also during myocardial ischemia. For example, in a recent paper in this Journal, dispersion in action potential duration was measured in globally ischemic hearts. It was stated that “… an enhanced dispersion for repolarization is now well known to act as a substrate for arrhythmogenesis.”.

Postrepolarization Refractoriness in Acute Ischemia and After Antiarrhythmic Drug Administration

Ruben Coronel, Michiel J. Janse, Tobias Opthof, Arthur A.M. Wilde, Peter Taggart — 2012-03-19

We thank Drs. Pandit, Noujaim, and Jalife for their letter regarding our review on postrepolarization refractoriness (PRR). We had no intention of criticizing our colleagues, and we are well aware that the authors had earlier discussed the determinants of PRR. However, for the uninitiated, the phrase “an enhanced dispersion for repolarization is now well known to act as a substrate for arrhythmogenesis” may be confounding when the authors extrapolate “enhanced dispersion of repolarization” to increased arrhythmogenesis in the setting of acute ischemia. Under these conditions, recovery from inexcitability must be taken into account. Unintentionally or not, our colleagues have suggested that the increase in dispersion of repolarization, which is clearly arrhythmogenic in normoxic conditions, is similarly arrhythmogenic during acute myocardial ischemia. Indeed, in the cited article, the word “refractory” or “refractoriness” is not used, and in the limitation section of their paper they write: “We have not studied arrhythmogenesis per se in this model of global ischemia. This will require more systematic and extensive studies, with properly timed and spatially appropriate (with respect to the APD gradient) triggers for initiating arrhythmias.” This suggests that the authors expect that extrastimuli delivered at a site with a short action potential duration (APD) close to a steep gradient in APD will provoke arrhythmias. The problem is that dispersion in refractoriness may be very large in the absence of a gradient in APD and vice versa. In fact, during regional ischemia, the dispersion in APD between normal myocardium (long action potential) and ischemic myocardium (short action potential) does not represent the gradient in repolarization (as a result of regional conduction slowing), which in turn may be more than compensated by PRR in the ischemic region. This is what we tried to underscore in our review.