Iqwal Mangat

Long-Term Comparison of the Implantable Cardioverter Defibrillator Versus Amiodarone Eleven-Year Follow-Up of a Subset of Patients in the Canadian Implantable Defibrillator Study (CIDS)

Background—The implantable cardioverter defibrillator (ICD) is superior to amiodarone for secondary prophylaxis of sudden cardiac death. However, the magnitude of this benefit over long-term follow-up is not known. Thus, our objective was to evaluate the long-term consequences of using amiodarone versus an ICD as first-line monotherapy in patients with a prior history of sustained ventricular tachycardia/ventricular fibrillation or cardiac arrest. Methods and Results—A total of 120 patients were enrolled at St Michael’s Hospital in the Canadian Implantable Defibrillator Study (CIDS) and were randomly assigned to receive either amiodarone (n=60) or an ICD (n=60). The treatment strategy was not altered after the end of CIDS unless the initial assigned therapy was not effective or was associated with serious side effects. After a mean follow-up of 5.6±2.6 years, there were 28 deaths (47%) in the amiodarone group, compared with 16 deaths (27%) in the ICD group (P =0.0213). Total mortality was 5.5% per year in the amiodarone group versus 2.8% per year in the ICD group (hazard ratio of amiodarone: ICD, 2.011; 95% confidence interval, 1.087 to 3.721; P =0.0261). In the amiodarone group, 49 patients (82% of all patients) had side effects related to amiodarone, of which 30 patients (50% of all patients) required discontinuation or dose reduction; 19 patients crossed over to ICD because of amiodarone failure (n=7) or side effects (n=12). Conclusions—In a subset of CIDS, the benefit of the ICD over amiodarone increases with time; most amiodarone-treated patients eventually develop side effects, have arrhythmia recurrences, or die.

The effect of vernakalant (RSD1235), an investigational antiarrhythmic agent, on atrial electrophysiology in humans.

Objectives: To determine the acute effects of vernakalant (RSD1235) on electrophysiologic (EP) properties in humans. Background: Vernakalant is an investigational mixed ion channel blocker that can terminate acute atrial fibrillation (AF) in humans at 2 to 5 mg/kg and may be more “atrial-selective” than available agents. Methods: Patients (N = 19; 53% male; age, 48 ± 11 years) underwent EP study before and after 25 minutes of intravenous vernakalant administration: 2 mg/kg over 10 min + 0.5 mg/kg/hr for 35 min or 4 mg/kg over 10 min + 1 mg/kg/hr for 35 min. EP measurements, including atrial refractory period (AERP) and ventricular refractory period (VERP), were obtained. Results: The lower dose prolonged AERP at 600, but not at 400 or 300 msec paced cycle length. The higher dose significantly prolonged AERP from 203 ± 31 msec to 228 ± 24 msec at 600 msec, 182 ± 30 msec to 207 ± 27 msec at 400 msec, and 172 msec ± 24 to 193 ± 21 msec at 300 msec. There was no significant prolongation of VERP at either dose or at any cycle length. There was a small but significant prolongation of AV nodal refractoriness; Wenckebach cycle length prolonged by 18 ± 12 msec (from baseline 343 ± 54 msec) at the higher dose (P < 0.05). Sinus node recovery time also increased by 123 ± 158 msec (from baseline 928 ± 237 msec) at the higher dose (P < 0.05). There was a slight prolongation of QRS duration at the higher dose, during ventricular pacing at CL = 400 msec (15 ± 15 msec, P = 0.0547). QT and HV intervals were unchanged. Conclusions: At doses similar to those tested clinically, vernakalant dose-dependently prolonged atrial refractoriness, prolonged AV nodal conduction and refractoriness, and slightly prolonged QRS duration, but it had no effect on ventricular refractoriness.

Clinical Predictors of Fidelis Lead Failure Report From the Canadian Heart Rhythm Society Device Committee

Background— Approximately 268 000 Fidelis leads were implanted worldwide until distribution was suspended because of a high rate of early failure. Careful analyses of predictors of increased lead failure hazard are required to help direct future lead design and also to inform decision making on lead replacement. We sought to perform a comprehensive analysis of all potential predictors in a multicenter study. Methods and Results— A total of 3169 Sprint Fidelis leads were implanted in 11 centers with a total of 251 failures. Lead failure rates at 3, 4, and 5 years were 5.3%, 10.6%, and 16.8%, respectively. The rate of lead failure continues to accelerate (P<0.001). There were 4 independent predictors of failure: center, sex, access vein, and previous lead failure. Women had a higher hazard of failure (hazard ratio 1.51; 95% confidence interval, 1.14–2.04; P=0.005). Both axillary and subclavian access increased the hazard of failure (P=0.007); hazard ratio for axillary was 1.94, (95% confidence interval, 1.23–3.04) and for subclavian 1.63 (95% confidence interval, 1.08–2.46). Previous lead failure increased the hazard of a subsequent Fidelis failure with a hazard ratio of 3.12 (95% confidence interval, 1.80–5.41; P<0.001). Conclusions— The rate of Fidelis failure continues to increase over time, with failures approaching 17% at 5 years. Women, patients with leads inserted via the subclavian or axillary vein, and those with a previous lead fracture were at greatest risk of Fidelis failure. Our data suggest that Fidelis replacement should be strongly considered at the time of generator replacement.Background— Approximately 268 000 Fidelis leads were implanted worldwide until distribution was suspended because of a high rate of early failure. Careful analyses of predictors of increased lead failure hazard are required to help direct future lead design and also to inform decision making on lead replacement. We sought to perform a comprehensive analysis of all potential predictors in a multicenter study. Methods and Results— A total of 3169 Sprint Fidelis leads were implanted in 11 centers with a total of 251 failures. Lead failure rates at 3, 4, and 5 years were 5.3%, 10.6%, and 16.8%, respectively. The rate of lead failure continues to accelerate ( P <0.001). There were 4 independent predictors of failure: center, sex, access vein, and previous lead failure. Women had a higher hazard of failure (hazard ratio 1.51; 95% confidence interval, 1.14–2.04; P =0.005). Both axillary and subclavian access increased the hazard of failure ( P =0.007); hazard ratio for axillary was 1.94, (95% confidence interval, 1.23–3.04) and for subclavian 1.63 (95% confidence interval, 1.08–2.46). Previous lead failure increased the hazard of a subsequent Fidelis failure with a hazard ratio of 3.12 (95% confidence interval, 1.80–5.41; P <0.001). Conclusions— The rate of Fidelis failure continues to increase over time, with failures approaching 17% at 5 years. Women, patients with leads inserted via the subclavian or axillary vein, and those with a previous lead fracture were at greatest risk of Fidelis failure. Our data suggest that Fidelis replacement should be strongly considered at the time of generator replacement. # Clinical Perspective {#article-title-32}

Complications Associated With Revision of Sprint Fidelis Leads Report From the Canadian Heart Rhythm Society Device Advisory Committee

Background— It has been observed that replacement of an implantable cardioverter-defibrillator generator in response to a device advisory may be associated with a substantial rate of complications, including death. The risk of lead revision in response to a lead advisory has not been determined previously. Methods and Results— Twenty-five implantable cardioverter-defibrillator implantation and follow-up centers from the Canadian Heart Rhythm Society Device Advisory Committee were surveyed to assess complication rates as a result of lead revisions due to the Sprint Fidelis advisory issued in October 2007. As of June 1, 2009, there had been 310 lead failures found in 6237 Sprint Fidelis leads in Canada (4.97%) over a follow-up of 40 months. There were 469 leads to be revised, 66% for confirmed fracture. Of the patients who underwent revision, 95% had a new lead inserted, whereas 4% had a pace/sense lead added. The lead was removed in 248 cases (53%), by simple traction in 61% and by laser lead extraction in 33%. Complications were encountered in 14.5% of the lead revisions; 7.25% of these were major, whereas 7.25% were minor. There were 2 deaths (0.43%). The overall risk of complications (19.8%) was greater in those who underwent lead removal at the time of revision than in those whose leads were abandoned (8.6%; P=0.0008). Conclusions— The overall rate of major complications that arose from lead revision due to the Sprint Fidelis advisory was significant. This must be taken into account when lead revision is planned in those patients who have not yet demonstrated an abnormality in lead performance.

Outcome of the Fidelis implantable cardioverter-defibrillator lead advisory: A report from the Canadian Heart Rhythm Society Device Advisory Committee

BACKGROUND The Medtronic Sprint Fidelis family of leads has recently been the subject of a widespread advisory. Lead failure rates are estimated at 2.3% at 30 months, 2.6 times the failure rate of the reference Medtronic 6947 lead. OBJECTIVE The purpose of this study was to contact pediatric and adult implantable cardioverter-defibrillator (ICD) implant centers across Canada to determine the short-term response to the October 15, 2007 Medtronic Fidelis lead advisory. METHODS All centers completed an 11-part survey to assess the frequency and presentation of lead failure, operator characteristics, and centers response. RESULTS Lead failure was noted in 80 (1.29%) of 6,181 patients at 21.0 months, with inappropriate shocks experienced in 45 (56%) of the 80 patients (overall risk 0.73%). No deaths were attributed to lead failure. Sensing was the primary form of failure, seen in 60 leads (75%), with pacing failure in 10 (13%), and high-voltage failure in 15 (19%). Assessment of the previous routine ICD interrogation prior to the advisory or lead failure demonstrated evidence of altered lead performance in only 8 (10%) of the 80 leads. Inappropriate shocks typically were multiple (median 7, range 1-122), with a single shock seen in only 5 patients. Lead failure was noted in 18 of 23 centers, representing 89.8% of leads implanted, with at least one failure noted in 15 of 16 centers that implanted more than 200 leads. Forty-seven of the 135 operators in the 23 institutions implanted the 80 leads that subsequently failed. Only 16 operators were involved in more than a single lead that subsequently failed; seven operators participated in three or more leads that subsequently failed. Seven centers planned to replace leads in most pacing-dependent patients, and two centers planned to replace leads in patients unable to hear the alert tone. CONCLUSION This national experience suggests a Fidelis lead failure rate of 1.29% at 21 months, most often presenting with multiple inappropriate shocks without evidence of impending failure from routine lead follow-up. Lead failure did not appear to cluster around specific operators or around high-volume or low-volume implant centers.

Sex differences in implantable cardioverter-defibrillator outcomes: findings from a prospective defibrillator database.

BACKGROUND Sex differences in the use and outcomes of implantable cardioverter-defibrillators (ICDs) have not been fully studied. OBJECTIVE To examine potential sex differences in ICD implantation and device outcomes. DESIGN Health payer-mandated, prospective study of patients referred for ICD implantation, with comprehensive, longitudinal follow-up for complications, deaths, and device outcomes. SETTING 18 ICD implantation and follow-up centers in Ontario, Canada. PATIENTS 6021 patients (4733 men) referred for ICD implantation from February 2007 to July 2010. MEASUREMENTS Multivariate-adjusted ICD implantation rate, complications up to day 45, multivariate-adjusted complications, device outcomes (including appropriate shocks and therapies), and deaths occurring during 1-year follow-up. RESULTS Rates of ICD implantation were similar in men and women (relative risk, 0.99 [95% CI, 0.97 to 1.02]; P = 0.60). However, women were significantly more likely to experience major complications by 45 days (odds ratio, 1.78 [CI, 1.24 to 2.58]; P = 0.002) and 1 year (hazard ratio [HR], 1.91 [CI, 1.48 to 2.47]; P < 0.001) after implantation. Occurrence of any major or minor complication was also increased in women at both 45-day follow-up (odds ratio, 1.50 [CI, 1.12 to 2.00]; P = 0.006) and 1-year follow-up (HR, 1.55 [CI, 1.25 to 1.93]; P < 0.001). After implantation, women were less likely than men to receive appropriate ICD shock (HR, 0.69 [CI, 0.51 to 0.93]; P = 0.015) or appropriate therapy via shock or antitachycardia pacing (HR, 0.73 [CI, 0.59 to 0.90]; P = 0.003). Total mortality among defibrillator recipients did not differ between men and women (HR, 1.00 [CI, 0.64 to 1.55]; P = 0.99). LIMITATION The differential effects of sex on prereferral events were not examined. CONCLUSION Although ICD implantation rates were similar after referral to an electrophysiologist, women who underwent ICD implantation had greater risks for complications and were less likely to experience appropriate ICD-delivered therapies than men. PRIMARY FUNDING SOURCE Canadian Institutes of Health Research and Ontario Ministry of Health and Long-Term Care.

n-3 Polyunsaturated fatty acids alter expression of fibrotic and hypertrophic genes in a dog model of atrial cardiomyopathy.

BACKGROUND We previously showed that omega-3 polyunsaturated fatty acids (PUFAs) reduce vulnerability to atrial fibrillation (AF). The mechanisms underlying this effect are unknown. OBJECTIVE The purpose of this study was to use a genome-wide approach to identify gene expression profiles involved in a new model of AF vulnerability and to determine whether they were altered by PUFA therapy. METHODS Thirty-six dogs were randomized evenly into three groups. Two groups were paced using simultaneous atrioventricular pacing (SAVP) at 220 bpm for 14 days to induce atrial enlargement, fibrosis, and susceptibility to AF. One group was supplemented with oral PUFAs (850 mg/day) for 21 days, commencing 7 days before the start of pacing (SAVP-PUFAs). The second group received no PUFAs (SAVP-No PUFAs). The remaining dogs were unpaced, unsupplemented controls (CTRL). Atrial tissue was sampled at the end of the protocol. Gene expression was analyzed in four dogs randomly selected from each group (n = 12) via microarray. Results were confirmed with quantitative real-time polymerase chain reaction (RT-PCR) and histology on all 36 dogs. RESULTS Microarray or quantitative RT-PCR results showed that SAVP-No PUFAs dogs had significantly increased mRNA levels of protein kinase B (Akt), epidermal growth factor (EGF), JAM3, myosin heavy chain alpha (MHCalpha), and CD99 and significantly decreased levels of Smad6 compared with CTRL dogs. Quantitative RT-PCR showed that PUFA supplementation was associated with significant down-regulation of Akt, EGF, JAM3, MHCalpha, and CD99 levels compared with SAVP-No PUFAs dogs. CONCLUSION The effect of PUFAs on these fibrosis, hypertrophy, and inflammation related genes suggests that, in this model, PUFA-mediated prevention of AF may be due to attenuation of adverse remodeling at the genetic level in response to mechanical stress.

Failure rate of the Riata lead under advisory: A report from the CHRS Device Committee

BACKGROUND A unique form of lead failure has been described in the Riata (8-F) and Riata ST (7-F) silicone defibrillation lead degradation of the outer insulation, resulting in the externalization of conductor cables. OBJECTIVE To assess rates of lead revision due to lead failure in Riata leads affected by the Riata advisory. METHODS Nineteen implantable cardioverter-defibrillator implant and follow-up centers were surveyed. RESULTS As of March 1, 2012, there were 5043 known affected leads implanted in Canada. Data on 4358 (86.4%) leads were obtained; 65.3% of these were Riata (8-F) and 32.4% were Riata ST (7-F) leads. The median time from implant to last follow-up was 5 years. Electrical abnormalities were reported in 4.6% of the affected leads; 8.0% of these were found to have concomitant radiographic evidence of externalization. The rate of electrical failure was higher in the 8-F (5.2%) vs 7-F (3.3%) leads (P = .007). Oversensing with or without inappropriate shocks was reported in 39.8% of the leads with confirmed failure. Abnormally high or low impedance values (29.9%) and elevated pacing capture thresholds (43.8%) were frequently reported. One death (0.5%) attributed to lead failure was reported. Among the leads that were replaced, 21% were extracted. Two major complications (1.0%) were attributed to extraction of these leads. CONCLUSIONS The overall rate of lead failure in the Riata (8-F) and Riata ST (7-F) leads is higher than previously reported by using passive surveillance data. The impact of recent advisories related to these leads is not yet apparent.

Do vegetarians have to eat fish for optimal cardiovascular protection

Interest in the cardiovascular protective effects of n-3 (omega-3) fatty acids has continued to evolve during the past 35 y since the original research describing the low cardiovascular event rate in Greenland Inuit was published by Dyerberg et al. Numerous in vitro experiments have shown that n-3 fatty acids may confer this benefit by several mechanisms: they are antiinflammatory, antithrombotic, and antiarrhythmic. The n-3 fatty acids that have received the most attention are those that are derived from a fish source: namely, the longer-chain n-3 fatty acids eicosapentaenoic acid (EPA; 20:5n-3) and docosahexaenoic acid (DHA; 22:6n-3). More limited data are available on the cardiovascular effects of n-3 fatty acids derived from plants such as alpha-linolenic acid (ALA; 18:3n-3). Observational data suggest that diets rich in EPA, DHA, or ALA do reduce cardiovascular events, including myocardial infarction and sudden cardiac death; however, randomized controlled trial data are somewhat less clear. Several recent meta-analyses have suggested that dietary supplementation with EPA and DHA does not provide additive cardiovascular protection beyond standard care, but the heterogeneity of included studies may reduce the validity of their conclusions. No data exist on the potential therapeutic benefit of EPA, DHA, or ALA supplementation on those individuals who already consume a vegetarian diet. Overall, there is insufficient evidence to recommend n-3 fatty acid supplementation for the purposes of cardiovascular protection; however, ongoing studies such as the Alpha Omega Trial may provide further information.

Effects of Chronic Gap Junction Conduction-Enhancing Antiarrhythmic Peptide GAP-134 Administration on Experimental Atrial Fibrillation in Dogs

Background—Abnormal intercellular communication caused by connexin dysfunction may contribute to atrial fibrillation (AF). The present study assessed the effect of the gap junction conduction–enhancing antiarrhythmic peptide GAP-134 on AF inducibility and maintenance in a dog model of atrial cardiomyopathy. Methods and Results—Twenty-four dogs subject to simultaneous atrioventricular pacing (220 bpm for 14 days) were randomly assigned to placebo treatment (PACED-CTRL; 12 dogs) or oral GAP-134 (2.9 mg/kg BID; PACED-GAP-134; 12 dogs) starting on day 0. UNPACED-CTRL (4 dogs) and UNPACED-GAP-134 (4 dogs) served as additional control groups. Change in left atrial (LA) systolic area from baseline to 14 days was calculated using transoesophageal echocardiography. At 14 days, animals underwent an open-chest electrophysiological study. PACED-CTRL dogs (versus UNPACED-CTRL) had a shorter estimated LA wavelength (8.0±1.4 versus 24.4±2.5 cm, P<0.05) and a greater AF vulnerability (mean AF duration, 1588±329 versus 25±34 seconds, P<0.05). Oral GAP-134 had no effect on AF vulnerability in UNPACED dogs. Compared with PACED-CTRL dogs, PACED-GAP-134 dogs had a longer estimated LA wavelength (10.2±2.8 versus 8.0±1.4 cm, respectively, P<0.05). Oral GAP-134 did not significantly reduce AF inducibility or maintenance in the entire group of 24 PACED dogs; in a subgroup of dogs (n=11) with less than 100% increase in LA systolic area, oral GAP-134 reduced AF induction from 100% to 40% and mean AF duration from 1737±120 to 615±280 seconds (P<0.05). Conclusions—Oral GAP-134 reduces pacing-induced decrease in LA wavelength and appears to attenuate AF vulnerability in dogs with less atrial mechanical remodeling. Gap junction modulation may affect AF in some circumstances.