This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Scheinman, M. M. Articles by Keung, E. Search for Related Content PubMed PubMed Citation Articles by Scheinman, M. M. Articles by Keung, E.

YEAR IN CARDIOLOGY SERIES

The Year in Review of Clinical Cardiac Electrophysiology

Melvin M. Scheinman, MD, FACC^_*,_* and Edmund Keung, MD

^_* Cardiac Electrophysiology, University of California San Francisco, San Francisco, California
Veterans Affairs Medical Center, San Francisco, California.

Manuscript received February 12, 2008; accepted February 22, 2008.

^_* Reprint requests and correspondence: Dr. Melvin M. Scheinman, University of California San Francisco, 500 Parnassus Avenue, Box 1354, San Francisco, California 94143. (Email: scheinman{at}medicine.ucsf.edu).

	Atrial Fibrillation (AF) and Atrial Flutter (AFL)

Top Atrial Fibrillation (AF) and... Ventricular Arrhythmias Cardiac Genetic Syndromes Cardiac Rhythm and Heart... References

The AF-CHF trial was designed as a multicenter, prospective study to determine whether maintenance of sinus rhythm reduced cardiovascular mortality compared with a rate-controlled strategy in patients with CHF and AF. Secondary pre-specified end points included total mortality, worsening heart failure, cerebrovascular accident, hospitalization, quality of life, and costs. A total of 1,376 patients were randomized during the course of a 4-year study period. Inclusion criteria included left ventricular ejection fraction (LVEF) <35% and 1 episode of documented AF within 6 months of enrollment. Atrial fibrillation was persistent in 69% of patients, and 31% were in New York Heart Association (NYHA) functional class III to IV. Patients were randomized to a rhythm-controlled arm and were treated with amiodarone as the initial drug choice and sotalol or dofetilide were used in selected cases. Repeated direct current cardioversions were used to maintain sinus rhythm. The rate control group was treated with digoxin and beta-blockers. Both groups received optimal medical management for heart failure, and both groups received anticoagulant therapy. The prevalence of sinus rhythm on follow-up examination was approximately 80% in the rhythm-controlled group. No significant difference was found in the primary outcome between the rhythm-controlled group versus the rate-controlled group (26.7% vs. 25.5%). Similarly, there was no difference in total mortality (31.8% vs. 32.9%), stroke (2.6% vs. 3.0%), or worsening heart failure (27.6% vs. 30.8%). The authors concluded that "rhythm control does not improve cardiovascular mortality when compared to rate control." The results of the AF-CHF trials, therefore, extend the original observation of the AFFIRM trials to those with AF and CHF. There appears to be no overriding need to maintain sinus rhythm in this subgroup as long as rate control is achieved.

In addition, several large drug trials were reported. For example, 2 large-scale trials of dronedarone (a homolog of amiodarone) for patients with AF or AFL were reported (3). The 2 studies had identical protocols, but one was conducted in Europe whereas the other was in non-European countries. The study protocol involved a multicenter, double-blind, placebo-controlled study for patients with paroxysmal AF or AFL but without evidence of class III or IV CHF. In both trials, the median time to arrhythmia recurrence was significantly greater for the treated groups (41 days vs. 96 days for the European group and 59 days vs. 158 days for the non-Europeans). Of further interest was the fact that there was no difference in the incidence of adverse side effects between the treated and placebo groups apart from a greater incidence of increased serum creatinine for the treated group. A previous trial that used dronedarone for patients with congestive heart failure (ANDROMEDA [Antiarrhythmic Trial with Dronedarone in Moderate-to-Severe Congestive Heart Failure Evaluating Morbidity Decrease] trial) was terminated prematurely because of increased mortality in the treated group. The current study did not address this important issue. In addition, we do not have a head-to-head comparison between this agent and amiodarone for this patient cohort. The lack of reported toxicity with respect to dronedarone is quite impressive.

Vernakalant (previously RSD-1235) has been the subject of several recent reports. Earlier trials of this agent assessing safety and efficacy (ACT [Atrial arrhythmia Conversion Trial] 1 and ACT 3]) (4) included a total of 575 patients. The overall conversion rates in response to intravenous vernakalant for those with recent-onset AF (3 h to 7 days) was 51.1% versus 38% for placebo (p < 0.0001). The median time to conversion ranged from 10 to 11 min. Stiell et al. (5) reported on the safety and efficacy of a recent open-labeled multicenter trial (ACT 4). This trial involved 236 patients of AF of >3 h duration. Of this group, 167 had AF of <7 days' duration. Of the patients with recent-onset AF (<7 days), 51% converted to sinus rhythm within a median time of 14 min. The conversion rate for those with AF of 8 days or longer was <10%. There were no reports of ventricular fibrillation or torsades in any of the reported vernakalant trials; however, nonsustained ventricular tachycardia (VT) was reported in 3.4% of patients within 2 h and in 6.4% at 2 to 24 h. A recent report of the AHA meeting also documented the safety and efficacy of intravenous vernakalant for patients with post-surgical AF (6).

The available data suggest that the intravenous form of vernakalant will be a welcome addition for treatment of patients with AF. Its mode of action appears unique in that it inhibits both the atrial ultra-rapid K⁺ current as well as frequency-dependent Na⁺ channels. Although its efficacy is similar to that of ibutilide, the safety profile appears to be superior. An oral preparation of vernakalant is in the early stages of study.

A recent prospective randomized study by Kafkas et al. (7) compared rates of conversion with sinus rhythm for those with recent-onset AF and AFL treated with either intravenous amiodarone versus intravenous ibutilide. For patients with either AF or AFL, intravenous ibutilide was significantly superior to amiodarone in conversion to sinus rhythm. This study is a potentially important one in view of the somewhat-puzzling popularity in use of intravenous amiodarone for acute management of patients with AF or AFL.

Researchers of a randomized prospective study (8) compared the use of oral amiodarone versus cavotricuspid ablation for patients with a first onset of AFL. The study comprised 104 patients randomized to the 2 treatment arms. The patients treated with ablation achieved significantly better success in terms of maintenance of sinus rhythm. This study extends previous observations favoring ablative therapy and extends these observations in support for early superiority of ablative treatment.

Azimilide is an experimental agent with properties that block the late outward K⁺ currents (Ikr and Iks blockade). Previous studies have shown that the use of azimilide may be effective in the maintenance of sinus rhythm after cardioversion (9). In a recent oral azimilide trial, 402 patients with AF/AFL (and 56 with paroxysmal supraventricular tachycardia) were enrolled (10). The authors found no significant difference in time to first recurrence between treated patients (38 days) and the placebo group (27 days). Of note was the occurrence of nonsustained VT (1 episode of torsades) in 4 patients, all in the treated group. The study suggests that oral azimilide would appear to have no role in the management of patients with AF, AFL, or paroxysmal supraventricular tachycardia.

	Ventricular Arrhythmias

Top Atrial Fibrillation (AF) and... Ventricular Arrhythmias Cardiac Genetic Syndromes Cardiac Rhythm and Heart... References

 
The ABCD (Alternans Before Cardioverter Defibrillator) trial.   The authors of early primary prevention trials used invasive electrophysiological (EP) testing to identify high-risk individuals (11,12). This approach resulted in excellent therapeutic efficacy (4 implantable cardioverter-defibrillators [ICDs] for each life saved) (13). More recent trials were constructed to avoid the need for invasive testing and assessed risk on the basis of reduced left ventricular ejection fraction (14,15). On the basis of these studies, patients with an ejection fraction (EF) of <35% were found to benefit from ICDs. Unfortunately, this approach required insertion of 15 to 17 ICDs to save one life. The rationale behind the ABCD trial (which was first reported at the AHA meeting in 2006) was to compare the relative efficacy of invasive EP testing with noninvasive microvolt alternans testing. The latter is a noninvasive spectral approach to assess very small (microvolt) beat-to-beat alternans of the T waves. Previous studies emphasized the powerful negative predictive accuracy of microvolt T-wave alternans (MTWA) therapy (16,17).

A total of 566 patients were enrolled from 43 centers. Inclusion characteristics were the presence of coronary artery disease, LVEF <40%, and nonsustained VT (3 beats). The study was powered to test the hypothesis that MTWA was noninferior to invasive EP testing in predicting events at 1 year. The study group consisted of 84% men, average age 65 ± 10 years with a mean LVEF of 0.28 ± 0.08. The MTWA was positive in 46%, negative in 29%, and indeterminate in 23%. The EP study was positive in 39% and negative in 61%. However, discordant results were found in 55% (i.e., MTWA+, EP–, or vice versa). A total of 65 patients met the end point of VT, ventricular fibrillation, or sudden cardiac death (10 patients).

Despite the discordant results, there was no difference in either the positive or negative predictive accuracy comparing EP-guided versus MTWA-guided therapy. The latter was defined by an indeterminate MTWA and + EP study. Of interest was the finding that Kaplan-Meier event rates comparing EP+ versus EP– groups remained significantly different for up to 2 years of follow-up, whereas MTWA-directed therapy proved predictive for only the first year. They found a synergistic relationship between EP and MTWA testing. The predicted event rate was markedly improved (12.6%) when both tests are positive and quite low (2%) when both are negative or normal. The therapeutic efficacy (appropriate shock) of implanting ICDs improved from 7% (using LVEF alone) to 66% in those with a positive EP study. Of note the efficacy of MTWA abnormality alone improves efficacy to 35%.

The authors concluded that in patients with coronary artery disease, nonsustained VT, and LVEF <35% MTWA is as effective as EP for prediction of events at 1 year. They found that the combination of MTWA and EP was synergistic in predicting outcome; however, the predictive value of MTWA is dissipated in the second year of follow-up. In contrast, Bartone et al. (18) found that a non-negative MTWA test proved to be a robust predictor of all-cause mortality for those with ischemic disease with a 36-month follow-up.

This represents an important prospective study because they were able to compare invasive with non-invasive testing. The negative predictive value of MTWA was supported but the positive predictive accuracy was quite poor (Fig. 2). What are the practical implications for the clinicians? A negative test tilts toward not inserting the defibrillator but at the expense of missing a small percentage of patients who might benefit. In addition, the data emphasize the rationale for the MTWA-directed approach (i.e., MTWA indeterminate EP+). No technique is perfect, and the ultimate use will be dependent on the clinical decision of the acceptable threshold for which patients should be treated. This, of course, is taking into account the importance of age and comorbidities.

Another recent trial that focused on the use of MTWA was presented at the annual American College of Cardiology meeting (19). This trial attempted to test whether abnormal MTWA predicts life-threatening arrhythmias in a MADIT (Multicenter Automatic Defibrillator Implant Trial)-II population. The study included 575 patients with a prior myocardial infarction and EF <30%, and the primary end points were appropriate ICD shocks or arrhythmic deaths. The population showed a mean EF of 24%, and most had a history of congestive heart failure. There was no significant difference in end points between the MTWA negative patients (10%) versus those with non-negative (positive and indeterminate) (13%). Furthermore, sub-group analyses showed that those patients with QRS <120 ms were at low risk regardless of MTWA result. Although the methodology and patient population of the MASTER trial differed from the ABCD trial it, nevertheless, suggests caution in the use of MTWA as a risk stratifier. In addition, a very thoughtful and critical appraisal of MTWA was recently published (20). They concluded that "the evidence for the use of MTWA in risk stratification of SCD is compelling in some aspects, principally its NPV [negative predictive value] in patients with ischemic LVSD [left ventricular systolic dysfunction]. However, the available evidence is not yet sufficient to allow its extrapolation to routine clinical use in large numbers of patients to determine whether primary prevention ICD implantation is indicated."

Another interesting report involved a study of ranolazine in patients with acute coronary ischemia (21). Ranolazine is a drug that was recently approved for management of patients with angina pectoris that is refractory to conventional therapy. The mechanism of the anti-ischemic action is not clear, but the effects of this drug on ion channel function have been clarified. Ranolazine has been found to be associated with mild prolongation of the QT interval. Electrophysiological studies have shown that ranolazine acts to block the late Na⁺ current (which would tend to shorten the QT) and to block Ikr current (which would tend to prolong the action potential duration and QT). The Ikr effect appears to predominate because the drug is associated with a mild QT prolonging effect. Furthermore, the effects on the Ikr current appear to predominate in epicardial and endocardial cells, whereas the Ina block predominates in mid-myocardial cells. Overall, the drug appears to decrease transmembrane repolarization heterogeneity. Blockage of the late Ina current would be expected to prevent systolic Ca²⁺ overload and might have antiarrhythmic properties. This reasoning was the underpinning for a recent trial, which randomized 6,560 patients with non–ST-segment elevation myocardial infarction acute coronary syndrome to receive either ranolazine or placebo (22). The patients underwent continuous electrocardiogram monitoring for 7 days after enrollment. A pre-specified set of arrhythmias was examined in blinded fashion by the Core lab. The major findings were a statistically significant decrease in the incidence of nonsustained VT lasting either 4 or 8 beats. For those treated with ranolazine, there was no difference in the incidence of sustained polymorphous VT compared with those treated with active drug (0.32%) versus placebo (0.22%; p = 0.46). The episodes of polymorphous VT appeared to be related to myocardial ischemia in both groups. There was no significant difference in either total mortality or in sudden death between groups. This was true even for those in the highest risk groups (i.e., CHF, severe ischemia). In addition, although the incidence of AF was less for the treated group, this was not statistically significant.

In summary, although the apparent finding of an antiarrhythmic effect is of interest, this alone is of limited practical value. The lessons learned from CAST (Cardiac Arrhythmia Suppression Trial) are evident. A drug that decreases premature ventricular complex density does not necessarily prolong life. The neutral effect of the drug on overall mortality is a testament to its safety. Its true role as an antiarrhythmic agent remains to be established.

	Cardiac Genetic Syndromes

Top Atrial Fibrillation (AF) and... Ventricular Arrhythmias Cardiac Genetic Syndromes Cardiac Rhythm and Heart... References

 
Some of the most striking advances in clinical cardiac EP continue to occur in the area of the genetic arrhythmia syndromes. In 2007, there was a spate of excellent basic and clinical studies further elucidating the long-QT syndrome (LQTS). The latter has occurred because of the fact that 70% to 80% of these patients may now be successfully genotyped and because of the availability of a large international registry for long-QT patients (23) allowing for phenotype-genotype correlations.

LQTS.   This syndrome was first described in 1957 by Jervell and Lange-Nielsen (24) and highlighted the association between congenital deafness, prolonged QT interval, and sudden death. It has been determined that gain of function of Na⁺ channels (encoded by SCN5A) or decrease in function of the delayed k⁺ rectifier currents Iks (slow activation K⁺ current) or Ikr (rapidly activated k⁺ current) are the main causes of the LQTS. The mutations involve either the membrane-spanning subunits or the associated proteins attached to these channels. The vast majority of patients will have genetic abnormalities involving k⁺ channels (Iks–LQT1), (Ikr–LQT2), or Na⁺ channels SCN5A (LQT3) (25). Rare mutations of a gene encoding the L-type Ca²⁺ channel have been described.

The vast majority of known mutations involve genes that encode Iks and Ikr channels (85%), whereas SCN5A mutations make up approximately 13%. Compound mutations in the same or different genes occur in as many as 10% of genotype positive groups (26) and appear to be associated with a greater incidence of arrhythmias. A host of recent studies have focused on the ungenotyped 25% to 30% of LQTS patients (27–30). These studies have focused on intron mutations or abnormalities in the exon splice sites. In addition, 2 newer mutations causing the LQT1 syndrome have been described, one involving the Yotiao protein complex (31), which produces a pattern similiar to LQT1 (Iks current), and the other resulting in an abnormality of alpha-1-syntrophin, which produces a LQT3 picture (32).

Newer clinical findings.   A number of studies have focused on genotype-phenotype interactions. For example, in LQT2 patients, mutations in the pore region of the KCNH2 gene are at increased risk for cardiac arrhythmias compared with those with nonpure mutations (33). One study focused on LQT patients between the ages of 18 and 40 years and found that female gender, LQT2, QTc >500 ms, and the presence of cardiac events (syncope, aborted sudden death) before the age of 18 years were associated with an increased risk of cardiac events in adulthood (34). In contrast, male adolescents between the ages of 10 and 12 years were at greater risk than female adolescents. Similarly, QTc duration and syncopal episodes were found to be risk factors for life-threatening events (35).

The beneficial effects of beta-blocker therapy have long been appreciated. More recent observations have focused on the fact the most pronounced beneficial effects are observed for those with LQT1 with decreased efficacy for those with LQT2 and especially for those with LQT3 or the Jervell-Lange-Nielsen syndrome (36), Another study focused on the effects of pregnancy on women with LQTc (37). It was found that the risk for cardiac events was reduced during pregnancy but that the 9-month post-partum period was identified as a high-risk period. However, treatment with beta-blockers mitigated the post-partum risk.

A recent study focused on a cohort of 27 children with LQTS who were treated with a defibrillator (38). Most of these patients were genotyped as LQT2 or LQT3 and underwent implantation after failed beta-blocker therapy. On follow-up, 5 (12%) had appropriate shocks and 4 had at least 1 inappropriate shock. None had recurrent shocks (electrical storm). This study highlights the emerging experience of automatic ICD therapy in the high-risk pediatric population. It is important to set the automatic ICD discharge rate at appropriate levels for active children to avoid inappropriate shocks incident to sinus tachycardia.

Finally, important insights were gained from a retrospective study in which the authors used post-mortem genetic testing on young individuals with sudden unexplained death. A total of 17 genetic mutations were found in 49 subjects studied (39). Ten were found to have abnormalities in genes associated with LQTS, and 7 had abnormalities in the RyR2 genes responsible for the syndrome of catecholaminergic polymorphous ventricular tachycardia. Additional studies have shown that the LQTS is implicated in 5% to 10% of infants with sudden infant death syndrome (40–42) or in stillbirth children (43).

	Cardiac Rhythm and Heart Failure Management Devices

Top Atrial Fibrillation (AF) and... Ventricular Arrhythmias Cardiac Genetic Syndromes Cardiac Rhythm and Heart... References

 
Driving with ICD.   Patients with ICDs often ask their physicians whether they can continue driving. Despite recent guidelines that suggest resumption of driving as soon as the surgical incision is healed, it remains a difficult and uncomfortable question because of patient and public safety concerns, impact on quality of life, and socioeconomic and legal ramifications. Recently, the TOVA (Triggers of Ventricular Arrhythmias) study provided some reassuring information on this matter when the investigators examined the impact of driving on ICD discharges among 1,188 ICD patients with class I and II implant indications (44). The relative risk of shocks for VT/ventricular fibrillation was only significantly increased during the 30-min period after driving. Most importantly, the risk of ICD shock was not greater during driving. Neither new implants (defined as <6 months implanted) nor indications (primary or secondary prevention) had an interactive effect on the analysis. The study also pointed out that 1 in 7 patients experiencing a shock actually had an auto accident. Precise guidelines for driving for patients with ICDs have been previously published (45).

Cardiac resynchronization therapy (CRT).   The investigators of the COMPANION (Comparison of Medical Therapy, Pacing and Defibrillation in Heart Failure) study performed a retrospective data analysis to determine whether class IV patients would benefit from cardiac resynchronization therapy with defibrillator (CRT-D, n = 83) or without defibrillator (CRT, n = 79) when compared with patients on optimal medical therapy (OPT, n = 55) (46). The studied patients had a very poor prognosis, as evidenced by a 44% mortality at the end of 1 year in the OPT group.

At 2 years, when compared with OPT, both CRT and CRT-D improved: 1) the time to all-cause mortality or first hospitalization, and 2) the time to all death or heart failure hospitalization. Only CRT-D benefited the time to sudden death: 25%, 16%, and 9% died of sudden cardiac death in year 2 for OPT, CRT, and CRT-D, respectively. The result suggested that CRT and CRT-D should be considered in ambulatory NYHA functional class IV patients with heart failure. The data confirmed once again that the ICD is effective in preventing sudden cardiac arrhythmic death even in NYHA functional class IV patients. As therapy devices for patients with severe heart failure, neither CRT nor CRT-D improved the time to heart failure death. It is plausible that the ventricles were too sick to allow for improvement in mechanical performance.

Results from small and nonrandomized studies have suggested that CRT may benefit patients with left ventricular mechanical dyssynchrony even in the presence of normal QRS duration. This unsettled issue was examined in a randomized nonblinded study (RethinQ: the Cardiac Resynchronization Therapy in Patients with Heart Failure and Narrow QRS) involving 172 patients with NYHA functional class III heart failure, an EF of 0.35, QRS duration of <130 ms, and ventricular dyssynchrony documented by tissue Doppler (47). One-half of the patients received a CRT-D and the other half received an ICD. At 6 months, there were no differences between the 2 groups in peak oxygen consumption, quality-of-life score, 6-min walk distance, and heart failure events requiring intravenous therapy. On the basis of these results, it was concluded that patients with heart failure and narrow QRS interval may not benefit from CRT. It remains to be seen whether this study defines the role of CRT in patients with narrow QRS complex. It is conceivable that the negative results were related to the short follow-up period and the identification method (M-mode echocardiography was not used in 96% of the patients). The study was not designed to examine common end points such as mortality and heart failure hospitalization.

ICD patients and risk stratification.   On the basis of a number of multicenter clinical studies, ICD implant indications have been greatly expanded since their introduction. At the same time, we have been trying to refine our patient selection criteria with the ultimate goal of implanting ICD only in patients who will need therapy. The MUSTT (Multicenter Unsustained Tachycardia Trial) investigators retrospectively examined their database to construct a risk-stratification model to better predict mortality risk and sudden death in patients with coronary artery disease, LVEF 0.40, nonsustained VT, and inducible ventricular sustained VT, with the goal of improving ICD patient selection (48).

The following risk factors were found to have a statistically significant association with total mortality: NYHA functional class at the time of enrollment, left bundle branch block or interventricular conduction delay, history of heart failure, LVEF, age, atrial fibrillation at the time of enrollment, inducible VT, and previous coronary artery bypass grafting. Arrhythmic death was associated with left bundle branch block or interventricular conduction delay, heart failure, LVEF, inducible VT, nonsustained VT 10 days beyond coronary artery bypass grafting, and patients enrolled into the study as inpatient. Using patient survival data in the MUSTT database and assigning points to each risk factor, a model was created to best predict the survival of patients in the MUSTT database.

As pointed out by the accompanying editorial, the use of this risk-stratification model is severely limited by the fact that it is based on patients who had inducible VT by EP study, an approach that is rarely used in clinical practice (49). Renal function, which had been identified as an independent predictor of mortality, was not found to be a risk factor in the analysis (50). Nevertheless, the model showed that several other variables carried a similar prognostic significance as LVEF: in the absence of other risk factors, an LVEF 0.30 was associated with a 2-year total mortality of only 5%.

Analysis of patients in the conventional therapy arm of MADIT-II identified 5 risk factors in predicting all-cause mortality: 1) New York Heart Association functional class >II; 2) age >70 years; 3) blood urea nitrogen >26 mg/dl; 4) QRS duration >0.12 s; and 5) AF (51). The use of ICD therapy reduced 2-year mortality by 49% among patients with 1 risk factor and offered no benefit in patients with no risk factor (approximately one-third of the patients, 2-year mortality of only 8%) and with marked renal dysfunction (blood urea nitrogen >50 mg/dl and/or creatinine >2.5 mg/dl). Similar to the MUSTT analysis, the investigators observed that LVEF may not be the only selection criterion for ICD therapy in patients with ischemic cardiomyopathy.

Trouble with high-voltage (HV) ICD leads.   The reliability of HV defibrillator leads was called to attention by a performance report on 990 leads implanted between 1992 to 2005 from a single registry (52). The survival rate was disturbingly low: 90%, 85%, and 60% at 3, 4, and 8 years, respectively. The failure rate increased progressively with time. The adverse events included insulation defects (56%), lead fractures (12%), loss of ventricular capture (11%), abnormal lead impedance (10%), and sensing failure (10%). It is important to note that two-thirds of lead defects could be detected by routine device interrogation, underscoring the importance of post-implant device follow-up. The failure rate may be overestimated because the analysis included complications (such as T-wave oversensing, exit block, and R-wave under-sensing) that may not always relate to intrinsic lead defects. This report was soon followed by a major Food and Drug Administration class I recall of the Medtronic Fidelis (Medtronic, Minneapolis, Minnesota) leads and reports on a still unsettled complication in another HV lead family.

Hauser et al. (53) reported a greater-than-expected rate of failure in the Medtronic Sprint Fidelis model 6949 HV lead. Six of 583 Medtronic Sprint Fidelis model 6949 implanted between September 2004 and February 2007 failed over the course of 31 months (96% survival at 33 months). Only 1 of 285 Medtronic Sprint Quattro model 6847 failed over the course of 65 months (approximately 99% survival at 65 months). Analysis of the Food and Drug Administration Manufacturers User Facility Device Experience database and a review of the manufacturer's analyses showed that the most frequently reported defects for the Sprint Fidelis HV leads were fracture of the pace-sense conductor or coil and the HV conductor, leading to high impedances, noncapture, and inappropriate shocks (in response to nonphysiological noises). Because both the Sprint Fidelis and the Sprint Quattro leads used the same materials and construction, the cause for the high failure rate was postulated to be the small diameter (6.3 F) of the Sprint Fidelis lead, which lowered the conductors' tolerance to physical stress. In October 2007, Medtronic announced that the Sprint Fidelis lead had been withdrawn from the market and the U.S. Food and Drug Administration placed these leads (268,000 leads implanted worldwide) in a class I recall. Medtronic analyses confirmed that the root cause was lead fracture and reported a 30-month survival rate of 97.7% for the Fidelis leads, compared with 99.4% for the larger Sprint Quattro leads (54).

Meanwhile, an entirely different potential complication confronts another HV lead. In a single-center, retrospective analysis of 2 families of HV leads (Riata 1580/1581 and 1590/1591, St. Jude Medical, Sylmar, California and Sprint Fidelis 6949, Medtronic), the investigators observed a significantly greater incidence of subacute lead perforation (1 to 10 days post-implant) with the Riata leads as compared with the Sprint Fidelis leads (55). Five perforations occurred in 120 Riata leads, whereas none occurred in 111 Sprint Fidelis leads.

However, the safety issue associated with the Riata leads or any small-diameter leads has yet to be established. The smaller lead diameter cannot be the root cause of the perforation problem because the Medtronic Sprint Fidelis leads have similar size. Lead perforation is a recognized potential complication of implantation (0.1% to 0.8% for pacemaker leads and 0.6% to 5.2% for ICD leads) (56). It has been usually attributed to patients' medical conditions and to implant techniques, especially when the data were from a single center. However, since the publication of this report, several case reports describing acute and delayed (>30 days) perforation with the small-diameter Riata HV leads have been published (57–59). On the other hand, analyses performed by researchers at the St. Jude Medical Cardiac Rhythm Management Division do not suggest a greater incidence of perforation (60). Verbal and written incidence reports and returned product analysis showed perforation rates of 0.057% for 86,000 Riata 8-F leads and 0.157% for 35,000 implanted 7-F leads. The overall perforation rate for the Riata leads was 0.33% to 0.34% in 2 registries administered by researchers from the St. Jude Medical Cardiac Rhythm Management Division (ACT and OPTIMUM). At this point, more data from multiple sources will be needed before we can definitively identify if these leads are indeed unsafe.

	References

Top Atrial Fibrillation (AF) and... Ventricular Arrhythmias Cardiac Genetic Syndromes Cardiac Rhythm and Heart... References

 
1. Roy D, for the AF-CHF Investigators. Atrial fibrillation in congestive heart failure trial. Paper presented at: the American Heart Association meeting; November 6, 2007; Orlando, FL.

2. Wyse DG, Waldo AL, DiMarco JP, et al. Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) Investigators. A comparison of rate control and rhythm control in patients with atrial fibrillation. N Engl J Med 2002;347:1825-1833.[Abstract/Free Full Text]

3. Singh BN, Connolly SJ, Crijns HJ, et al. EURIDIS and ADONIS Investigators Dronedarone for maintenance of sinus rhythm in atrial fibrillation or flutter N Engl J Med 2007;357:987-999.[Abstract/Free Full Text]

4. Torp-Pedersen C, Roy D, Pratt C, et al. Efficacy and safety of vernakalant (RSD1235 injection) in the treatment of atrial fibrillation: combined analysis of two phase 3 trials. Paper presented at: the European Society of Cardiology World Congress of Cardiology 2006; September 2–6, 2006; Barcelona, Spain.

5. Stiell, I, Roy D, Pratt C. et al. Vernakalant hydrochloride injection (RSD 1235) effectively converts acute atrial fibrillation to sinus rhythm independent of background use of oral rate- or rhythm-control medications. Paper presented at: the 37th Annual Scientific Assembly of the American College of Emergency Physicians; October 15–18, 2006; New Orleans, LA.

6. Kowey PR, Roy D, Pratt DM, et al. Efficacy and safety of vernakalant hydrochloride for the treatment of atrial fibrillation after valvular or coronary artery bypass surgery(abstr) Circulation 2007;116:11-636.

7. Kafkas NV, Patsilinakos SP, Mertzanos GA, et al. Conversion efficacy of intravenous ibutilide compared with intravenous amiodarone in patients with recent-onset atrial fibrillation and atrial flutter Int J Cardiol 2007;118:321-325.[CrossRef][Web of Science][Medline]

8. DaCosta A, Thevenin J, Roche F, et al. Loire-Ardèche-Drôme-Isère-Puy-de-Dôme Trial of Atrial Flutter Investigators Results from the Loire-Ardèche-Drôme-Isère-Puy-de-Dôme (LAPID) trial on atrial flutter, a multicentric prospective randomized study comparing amiodarone and radiofrequency ablation after the first episode of symptomatic atrial flutter Circulation 2006;114:1676-1681.[Abstract/Free Full Text]

9. Kerr CR, Connolly SJ, Kowey P, et al. Efficacy of azimilide for the maintenance of sinus rhythm in patients with paroxysmal atrial fibrillation in the presence and absence of structural heart disease Am J Cardiol 2006;98:215-218.[CrossRef][Web of Science][Medline]

10. Page RL, Pritchett EL, Connolly S, Wilkinson WE, SVA-4 Investigators Azimilide for the treatment of atrial fibrillation, atrial flutter, and paroxysmal supraventricular tachycardia: results of a randomized trail and insights on the concordance of symptoms and recurrent arrhythmias J Cardiovasc Electrophysiol 2007;19:172-177.[CrossRef][Web of Science][Medline]

11. Moss AJ, Hall WJ, Cannom DS, et al. Improved survival with an implanted defibrillator in patients with coronary disease at high risk for ventricular arrhythmia. Multicenter Automatic Defibrillator Implantation Trial Investigators. N Engl J Med 1996;335:1933-1940.[Abstract/Free Full Text]

12. Buxton AE, Lee KL, Fisher JD, Josephson ME, Prystowsky EN, Hafley G. A randomized study of the prevention of sudden death in patients with coronary artery disease. Multicenter Unsustained Tachycardia Trial Investigators. N Engl J Med 1999;341:1882-1890.[Abstract/Free Full Text]

13. Mushlin AI, Hall WJ, Zwanziger J, et al. The cost-effectiveness of automatic implantable cardiac defibrillators: results from MADIT. Multicenter Automatic Defibrillator Implantation Trial. Circulation 1998;97:2129-2135.[Abstract/Free Full Text]

14. Moss AJ, Zareba W, Hall WJ, et al. Multicenter Automatic Defibrillator Implantation Trial II Investigators Prophylactic implantation of a defibrillator in patients with myocardial infarction and reduced ejection fraction N Engl J Med 2002;346:877-883.[Abstract/Free Full Text]

15. Bardy GH, Lee KL, Mark DB, et al. Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT) Investigators Amiodarone or an implantable cardioverter-defibrillator for congestive heart failure N Engl J Med 2005;352:225-237.[Abstract/Free Full Text]

16. Hohnloser SH, Ikeda T, Bloomfield DM, Dabbous OH, Cohen RJ. T-wave alternans negative coronary patients with low ejection and benefit from defibrillator implantation Lancet 2003;362:125-126.[CrossRef][Web of Science][Medline]

17. Bloomfield DM, Steinman RC, Namerow PB, et al. Microvolt T-wave alternans distinguishes between patients likely and patients not likely to benefit from implanted cardiac defibrillator therapy: a solution to the Multicenter Automatic Defibrillator Implantation Trial (MADIT) II conundrum Circulation 2004;110:1885-1889.[Abstract/Free Full Text]

18. Bartone CL, Chan PS, Schneider J, Chow T. Lack of time dependence of microvolt T-wave alternans prediction(abstr) Circulation 2007;116:11-635.

19. Cleland JG, Coletta AP, Abdellah AT, Cullington D, Clark AL, Rigby AS. Clinical trials update from the American Heart Association 2007: CORONA, RethinQ, MASCOT, AF-CHF, HART, MASTER, POISE and stem cell therapy Eur J Heart Fail 2008;1:102-108.

20. Myles RC, Jackson CE, Tsorlalis I, Petrie MC, McMurray JJ, Cobbe SM. Is microvolt T-wave alternans the answer to risk stratification in heart failure Circulation 2007;116:2984-2991.[Free Full Text]

21. Morrow DA, Scirica BM, Karwatowska-Prokopczuk E, et al. MERLIN-TIMI 36 Trial Investigators Effects of ranolazine on recurrent cardiovascular events in patients with non–ST-elevation acute coronary syndromes JAMA 2007;297:1775-1783.[Abstract/Free Full Text]

22. Scirica BM, Morrow DA, Hod H, et al. Effect of ranolazine, an antianginal agent with novel electrophysiological properties, on the incidence of arrhythmias in patients with non–ST-segment-elevation acute coronary syndrome Circulation 2007;116:1647-1652.[Abstract/Free Full Text]

23. Napolitano C, Priori SG, Schwartz PJ, et al. Genetic testing in the long QT syndrome JAMA 2005;294:2975-2980.[Abstract/Free Full Text]

24. Jervell A, Lange-Nielsen F. Congenital deaf mutism, functional heart disease with prolongation of the QT interval and sudden death Am Heart J 1957;54:59-68.[CrossRef][Web of Science][Medline]

25. Tester DJ, Will ML, Haglund CM, Ackerman MJ. Compendium of cardiac channel mutations in 541 consecutive unrelated patients referred for long QT syndrome genetic testing Heart Rhythm 2005;2:507-517.[CrossRef][Web of Science][Medline]

26. Westenskow P, Splawski I, Timothy KW, Keating MT, Sanguinetti MC. Compound mutations: a common cause of severe long-QT syndrome Circulation 2004;109:1834-1841.[Abstract/Free Full Text]

27. Arking DE, Pfeufer A, Post W, et al. A common genetic variant in the NOS1 regulator NOS1AP modulates cardiac repolarization Nat Genet 2006;38:644-651.[CrossRef][Web of Science][Medline]

28. Koopmann TT, Alders M, Jongbloed RJ, et al. Long QT syndrome caused by a large duplication in the KCNH2 (HERG) gene undetectable by current polymerase chain reaction-based exon-scanning methodologies Heart Rhythm 2006;3:52-55.[CrossRef][Web of Science][Medline]

29. Rossenbacker T, Schollen E, Kuipéri C, et al. Unconventional intronic splice site mutation in SCN5A associates with cardiac sodium channelopathy J Med Genet 2005;42:e29.[Abstract/Free Full Text]

30. Padgett RA, Grabowski PJ, Konarska MM, Seiler S, Sharp PA. Splicing of messenger RNA precursors Annu Rev Biochem 1986;55:1119-1150.[CrossRef][Web of Science][Medline]

31. Chen L, Marquardt ML, Tester DJ, Sampson K, Ackerman MJ, Kass RS. An inherited mutation of AKAP9 (Yotiao) causes long QT syndrome (LQTS)(abstr) Circulation 2007;116:11-653.

32. Vatta M, Ai T, Wu G, et al. A novel variant of alpha-1-syntrophin may cause long-QT syndrome(abstr) Circulation 2007;116:11-653.

33. Moss AJ, Zareba W, Kaufman ES, et al. Increased risk of arrhythmic events in long-QT syndrome with mutations in the pore region of the human ether-a-go-go-related gene potassium channel Circulation 2002;105:794-799.[Abstract/Free Full Text]

34. Sauer AJ, Moss AJ, McNitt S, et al. Long QT syndrome in adults J Am Coll Cardiol 2007;49:329-337.[Abstract/Free Full Text]

35. Hobbs JB, Peterson DR, Moss AJ, et al. Risk of aborted cardiac arrest or sudden cardiac death during adolescence in the long-QT syndrome JAMA 2006;296:1249-1254.[Abstract/Free Full Text]

36. Priori SG, Napolitano C, Schwartz PJ, et al. Association of long QT syndrome loci and cardiac events among patients treated with β-blockers JAMA 2004;292:1341-1344.[Abstract/Free Full Text]

37. Seth R, Moss AJ, McNitt S, et al. Long QT syndrome and pregnancy J Am Coll Cardiol 2007;49:1092-1098.[Abstract/Free Full Text]

38. Etheridge SP, Sanatani S, Cohen MI, Albaro CA, Saarel EV, Bradley DJ. Long QT syndrome in children in the era of implantable defibrillators J Am Coll Cardiol 2007;50:1341-1342.[Free Full Text]

39. Tester DJ, Ackerman MJ. Postmortem Long QT syndrome genetic testing for sudden unexplained death in the young J Am Coll Cardiol 2007;49:240-246.[Abstract/Free Full Text]

40. Arnestad M, Crotti L, Rognum TO, et al. Prevalence of long-QT syndrome gene variants in sudden infant death syndrome Circulation 2007;115:361-367.[Abstract/Free Full Text]

41. Cronk LB, Ye B, Kaku T, et al. Novel mechanism for sudden infant death syndrome: persistent late sodium current secondary to mutations in caveolin-3 Heart Rhythm 2007;4:161-166.[CrossRef][Web of Science][Medline]

42. Tester DJ, Ackerman MJ. Sudden infant death syndrome: how significant are the cardiac channelopathies? Cardiovasc Res 2005;67:388-396.[Abstract/Free Full Text]

43. Crotti L, Insolia R, Ghidoni A, et al. Long-QT syndrome as a cause of stillbirths(abstr) Circulation 2007;116:11-653.

44. Albert CM, Rosenthal L, Calkins H, et al. Driving and implantable cardioverter-defibrillator shocks for ventricular arrhythmias J Am Coll Cardiol 2007;50:2230-2240.

45. Lehmann MH, Saksena S. Implantable cardioverter defibrillators in cardiovascular practice: report of the Policy Conference of the North American Society of Pacing and Electrophysiology Pacing Clin Electrophysiol 1991;14:969-979.[CrossRef][Medline]

46. Linderfeld J, Feldman AM, Saxon L, et al. Effects of cardiac resynchronization therapy with or without a defibrillator on survival and hospitalization in patients with New York Heart Association class IV heart failure Circulation 2007;115:204-212.[Abstract/Free Full Text]

47. Beshai JF, Grimm RA, Nagueh SF, et al. Cardiac-resynchronization therapy in heart failure with narrow QRS complexes N Engl J Med 2007;357:2461-2471.[Abstract/Free Full Text]

48. Buxton AE, Lee KL, Hafley GE, et al. Limitation of ejection fraction for prediction of sudden death risk in patients with coronary artery disease J Am Coll Cardiol 2007;50:1150-1180.[Abstract/Free Full Text]

49. Anderson K. Risk assessment for defibrillation therapy. Il Trittico. J Am Coll Cardiol 2007;50:1158-1160.[Free Full Text]

50. Parkash R, Stevenson WG, Epstein LM, et al. Predicting early mortality after implantable defibrillator implantation: a clinical risk score for optimal patient selection Am Heart J 2006;151:397-403.[CrossRef][Web of Science][Medline]

51. Goldenberg I, Vyas AK, Hall J, et al. Risk stratification for primary implantation of a cardioverter-defibrillator in patients with ischemic left ventricular dysfunction J Am Coll Cardiol 2007;51:288-296.[CrossRef][Web of Science]

52. Kleemann T, Becker T, Doenges K, et al. Annual rate of transvenous defibrillation lead defects in implantable cardioverter-defibrillators over a period of >10 years Circulation 2007;115:2474-2480.[Abstract/Free Full Text]

53. Hauser R, Kallinen LM, Almquist AK, Gornick CC, Katsiyiannis WT. Early failure of a small-diameter high-voltage implantable Cardioverter-defibrillator lead Heart Rhythm 2007;4:892-896.[CrossRef][Web of Science][Medline]

54. Urgent Medical Device Information: Sprint Fidelis lead patient management recommendations. Medtronic, Inc., Minneapolis, Minnesota. October 15, 2007. Available at: http://www.medtronic.com/crm/performance/advisories/sprint-oct2007.html. Accessed March 26, 2008.

55. Danik SB, Mansour M, Singh J, et al. Increased incidence of subacute lead perforation noted with one implantable cardioverter-defibrillator Heart Rhythm 2007;4:439-442.[CrossRef][Web of Science][Medline]

56. Khan MH, Kahykin GJ, Ziada KM, Wilkoff B. Delayed lead perforation, a disturbing trend Pacing Clin Electrophysiol 2005;28:251-253.[CrossRef][Medline]

57. Kørivan L, Kozãk M, Vlanovã J, Sepi M. Right ventricular perforation with an ICD defibrillation lead managed by surgical revision and epicardial leads—case reports Pacing Clin Electrophysiol 2008;31:3-6.[Medline]

58. Fisher JD, Fox M, Kim SG, Goldstein D, Haramati LB. Asymptomatic anterior perforation of an ICD lead into subcutaneous tissues Pacing Clin Electrophysiol 2008;31:7-9.[Medline]

59. Satpathy R, Hee T, Esterbrooks D, Mohiuddin S. Delayed defibrillator lead perforation: An increasing phenomenon Pacing Clin Electrophysiol 2008;31:10-12.[Medline]

60. Carlson MD, Freedman RA, Levine PA. Lead perforation: incidence in registries Pacing Clin Electrophysiol 2008;31:13-15.[Medline]

This article has been cited by other articles:

				O. Ziv, E. Morales, Y.-k. Song, X. Peng, K. E. Odening, A. E. Buxton, A. Karma, G. Koren, and B.-R. Choi Origin of complex behaviour of spatially discordant alternans in a transgenic rabbit model of type 2 long QT syndrome J. Physiol., October 1, 2009; 587(19): 4661 - 4680. [Abstract] [Full Text] [PDF]

This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Scheinman, M. M. Articles by Keung, E. Search for Related Content PubMed PubMed Citation Articles by Scheinman, M. M. Articles by Keung, E.