Autosomal-dominant biventricular arrhythmogenic cardiomyopathy in a large family with a novel in-frame DSP nonsense mutation.

A novel autosomal-dominant in-frame deletion resulting in a nonsense mutation in the desmoplakin (DSP) gene was identified in association with biventricular arrhythmogenic cardiomyopathy across three generations of a large Caucasian family. Mutations that disrupt the function and structure of desmosomal proteins, including desmoplakin, have been extensively linked to familial arrhythmogenic right ventricular cardiomyopathy (ARVC). Analysis of data from 51 individuals demonstrated the previously undescribed variant p.Cys81Stop (c.243_251delCTTGATGCG) in DSP segregates with a pathogenic phenotype exhibiting variable penetrance and expressivity. The mutation's pathogenicity was first established due to two sudden cardiac deaths (SCDs), each with a biventricular cardiomyopathy identified on autopsy. Of the individuals who underwent genetic screening, 27 of 51 were heterozygous for the DSP mutation (29 total with two obligate carriers). Six of these were subsequently diagnosed with arrhythmogenic cardiomyopathy. An additional nine family members have a conduction disorder and/or myocardial structural changes characteristic of an evolving condition. Previous reports from both human patients and mouse studies proposed DSP mutations with a premature stop codon impart mild to no clinical symptoms. Loss of expression from the abnormal allele via the nonsense-mediated mRNA decay pathway has been implicated to explain these findings. We identified an autosomal-dominant DSP nonsense mutation in a large family that led to SCD and phenotypic expression of arrhythmogenic cardiomyopathy involving both ventricles. This evidence demonstrates the pathogenic significance of this type of desmosomal mutation and provides insight into potential clinical manifestations.

Eligibility and utilization of implantable cardioverter-defibrillators in a regional STEMI system.

BACKGROUND: Studies have shown mortality benefit for implantable cardioverter-defibrillators (ICDs) in ST-elevation myocardial infarction (STEMI) patients with reduced left ventricular ejection fraction (LVEF), but contemporary eligibility and appropriate utilization of ICDs is unknown. OBJECTIVE: The purpose of this study was to determine the contemporary eligibility and appropriate utilization of ICDs post-STEMI. METHODS: Using the prospective Minneapolis Heart Institute regional STEMI registry, LVEF before discharge and at follow-up were stratified into 3 groups: normal (LVEF ≥50%), mildly reduced (LVEF 35%-49%), and severely reduced (LVEF <35%). RESULTS: From March 2003 to June 2012, 3626 patients were treated. Patients with in-hospital death (n = 187), ICD in place (n = 21), negative cardiac biomarkers (n = 337), and undocumented in-hospital LVEF (n = 9) were excluded, leaving 3072 patients in the final analysis, including 1833 (59.7%) with LVEF ≥50%, 875 (28.5%) with LVEF between 35% and 49%, and 364 (11.8%) with LVEF <35% before hospital discharge. Overall, 1029 patients (33.5%) underwent follow-up echocardiography ≥40 days post-STEMI, including 140 of the 364 patients (38.5%) discharged with LVEF <35%. In total, 73 patients (7.1%) with follow-up echocardiography ≥40 days post-STEMI met criteria for an ICD (68 LVEF ≤30%, 5 LVEF 30%-35%, and New York Heart Association class II or greater). Only 26 of these patients (35.6%) underwent ICD placement within 1 year post-STEMI. Overall, only 10% to 15% of potentially eligible patients had an ICD implemented. CONCLUSION: Rates of ICD implantation in appropriate STEMI patients after 40 days are low. Strategies are needed to identify and expand access to these high-risk patients.

Peripheral artery disease is an independent predictor of mortality after implantable cardioverter-defibrillator implantation in patients with severe left ventricular dysfunction.

The impact of peripheral artery disease (PAD) on survival in implantable cardioverter defibrillator (ICD) patients is poorly understood. Thus, we assessed the risk of PAD in our adult ICD patients with left ventricular dysfunction (ejection fraction [EF] ≤35%). Survival was estimated with Kaplan-Meier method and compared by the log-rank test; a Cox proportional hazards model assessed the effects of clinical variables on survival. Average age and EF of 1399 patients were 67.0 ± 12.1 years and 23.8% ± 7.2%, respectively. The ICD patients with PAD had significantly worse survival than those without (unadjusted P < .0001). The multivariate predictors of survival at implant were (hazard ratio, HR [95% confidence interval]) age (HR 1.05 [1.04-1.07] P < .0001), PAD (HR 2.07 [1.53-2.80] P < .0001), class III/IV heart failure (HR 1.36 [1.06-1.76] P = .016), creatinine 1.4-2.0 mg/dL (HR 1.36 [1.05-1.76] P = .019), and creatinine ≥2.0 mg/dL (HR 2.01 [1.42-2.85] P < .0001). The PAD is an independent predictor of mortality and should be considered in the preimplant risk assessment.

Elevated T-wave alternans predicts nonsustained ventricular tachycardia in association with percutaneous coronary intervention in ST-segment elevation myocardial infarction (STEMI) patients.

INTRODUCTION: Successful reperfusion with primary percutaneous coronary intervention (PCI) can paradoxically elicit temporary vulnerability to ventricular arrhythmia. We examined whether T-wave alternans (TWA) level is correlated with nonsustained ventricular tachycardia (NSVT) incidence in association with PCI in patients with acute ST-segment elevation myocardial infarction (STEMI). METHODS AND RESULTS: We analyzed continuous 24-hour ambulatory electrocardiograms in 48 STEMI patients during and after successful primary PCI, achieving Thrombolysis in Myocardial Infarction (TIMI) grade 3 flow. TWA was measured using modified moving average method. Maximum TWA was elevated in patients with (N = 22) compared to without (N = 26) NSVT (75.1 ± 6.3 vs 49.9 ± 3.6 µV, P < 0.005) during the 22-hour monitoring period. TWA ≥ 60µV predicted NSVT with sensitivity of 77%; specificity, 73%; positive predictive value, 71%; and negative predictive value, 79%. Area under receiver operator characteristic curve (AUC) was 0.87 for maximum TWA in predicting NSVT. By comparison, ST-segment levels did not differ in patients with versus without NSVT and were not predictive (AUC = 0.52). TWA was elevated prior to PCI and remained elevated at 30 minutes after balloon inflation despite restoration of TIMI grade 3 flow in all patients, declining by 22 hours (P < 0.05). Maximum ST-segment levels decreased from before PCI to 30 minutes after balloon inflation. TWA is regionally specific, with higher values prior to PCI in precordial lead V5 than in V1 for left coronary lesions. CONCLUSIONS: TWA may be useful in identifying individuals at heightened risk for arrhythmia in association with primary PCI and can potentially signal time-dependent changes in arrhythmia vulnerability.

Therapeutic hypothermia after out-of-hospital cardiac arrest: evaluation of a regional system to increase access to cooling.

BACKGROUND: Therapeutic hypothermia (TH) improves survival and confers neuroprotection in out-of-hospital cardiac arrest (OHCA), but TH is underutilized, and regional systems of care for OHCA that include TH are needed. METHODS AND RESULTS: The Cool It protocol has established TH as the standard of care for OHCA across a regional network of hospitals transferring patients to a central TH-capable hospital. Between February 2006 and August 2009, 140 OHCA patients who remained unresponsive after return of spontaneous circulation were cooled and rewarmed with the use of an automated, noninvasive cooling device. Three quarters of the patients (n=107) were transferred to the TH-capable hospital from referring network hospitals. Positive neurological outcome was defined as Cerebral Performance Category 1 or 2 at discharge. Patients with non-ventricular fibrillation arrest or cardiogenic shock were included, and patients with concurrent ST-segment elevation myocardial infarction (n=68) received cardiac intervention and cooling simultaneously. Overall survival to hospital discharge was 56%, and 92% of survivors were discharged with a positive neurological outcome. Survival was similar in transferred and nontransferred patients. Non-ventricular fibrillation arrest and presence of cardiogenic shock were associated strongly with mortality, but survivors with these event characteristics had high rates of positive neurological recovery (100% and 89%, respectively). A 20% increase in the risk of death (95% confidence interval, 4% to 39%) was observed for every hour of delay to initiation of cooling. CONCLUSIONS: A comprehensive TH protocol can be integrated into a regional ST-segment elevation myocardial infarction network and achieves broad dispersion of this essential therapy for OHCA.

Lead integrity alert algorithm decreases inappropriate shocks in patients who have Sprint Fidelis pace-sense conductor fractures.

BACKGROUND: The Medtronic Sprint Fidelis high-voltage implantable cardioverter-defibrillator (ICD) lead is prone to fracture. The majority of fractures involve the pace-sense (P/S) conductors and may result in multiple inappropriate shocks. The Medtronic lead integrity alert (LIA) algorithm was designed to improve early detection of transient P/S conductor fractures and to decrease the incidence and number of inappropriate shocks. OBJECTIVE: The purpose of this prospective single-center study was to assess the effectiveness of the LIA algorithm for warning patients of an impending Sprint Fidelis P/S conductor fracture and for decreasing the incidence and number of inappropriate shocks. METHODS: The study population included all patients who had Sprint Fidelis leads and Medtronic ICD pulse generators that were implanted and followed at the Minneapolis Heart Institute. Patients were evaluated in the clinic every 3 to 4 months or by remote monitoring using the Medtronic CareLink system. When the LIA algorithm was released in August 2008, the RAMware was downloaded to the pulse generator of all patients with the Sprint Fidelis lead. Patients and family members received educational materials and were given a demonstration of the audible alerts. RESULTS: Between October 2004 and January 2010, 52 (11.3%) of 461 Sprint Fidelis leads failed in the study population. Inappropriate shocks were the first sign of lead failure in 18 (69%) of the 26 patients who did not have the LIA compared to 4 (17%) of 23 patients who had the LIA (P = .0004). Patients who experienced inappropriate shocks without the LIA received an average of 13.2 +/- 13.6 inappropriate shocks (range 2-54) versus 3.0 +/- 2.0 inappropriate shocks (range 2-6) in patients who had the LIA (P = .017). The audible alert was effective in 70% (16/23) and 35% (6/17) of patients with and without the LIA, respectively, whose alerts were programmed ON (P = .053). Overall, 8 (32%) of 25 patients whose audible alerts were triggered did not immediately hear or recognize the tone. CONCLUSION: The LIA appears to be an effective method for detecting most Sprint Fidelis lead fractures and for decreasing the incidence and number of inappropriate shocks. However, a better method for alerting patients and caregivers is needed.

Deaths and cardiovascular injuries due to device-assisted implantable cardioverter-defibrillator and pacemaker lead extraction.

AIMS: An estimated 10,000-15,000 pacemaker and implantable cardioverter-defibrillator (ICD) leads are extracted annually worldwide using specialized tools that disrupt encapsulating fibrous tissue. Additional information is needed regarding the safety of the devices that have been approved for lead extraction. The aim of this study was to determine whether complications due to device-assisted lead extraction might be more hazardous than published data suggest, and whether procedural safety precautions are effective. METHODS AND RESULTS: We searched the US Food and Drug Administration's (FDA) Manufacturers and User Defined Experience (MAUDE) database from 1995 to 2008 using the search terms 'lead extraction and death' and 'lead extraction and injury'. Additional product specific searches were performed for the terms 'death' and 'injury'. Between 1995 and 2008, 57 deaths and 48 serious cardiovascular injuries associated with device-assisted lead extraction were reported to the FDA. Owing to underreporting, the FDA database does not contain all adverse events that occurred during this period. Of the 105 events, 27 deaths and 13 injuries occurred in 2007-2008. During these 2 years, 23 deaths were linked with excimer laser or mechanical dilator sheath extractions. The majority of deaths and injuries involved ICD leads, and most were caused by lacerations of the right atrium, superior vena cava, or innominate vein. Overall, 62 patients underwent emergency surgical repair of myocardial perforations and venous lacerations and 35 (56%) survived. CONCLUSION: These findings suggest that device-assisted lead extraction is a high-risk procedure and that serious complications including death may not be mitigated by emergency surgery. However, skilled standby cardiothoracic surgery is essential when performing pacemaker and ICD lead extractions. Although the incidence of these complications is unknown, the results of our study imply that device-assisted lead extractions should be performed by highly qualified physicians and their teams in specialized centres.

Feasibility and safety of remote-controlled magnetic navigation for ablation of atrial fibrillation.

Radiofrequency ablation for atrial fibrillation (AF) involves complex catheter manipulation resulting in prolonged procedure time and fluoroscopy exposure. Remote magnetic navigation (RMN) represents a novel approach toward improving the ability to perform complex ablation. Forty patients underwent ablation for AF, 20 using RMN (NIOBE II, Stereotaxis, Inc) with a 4-mm-tip magnetic catheter (Celsius, Biosense Webster) and 20 using a conventional 8-mm-tip bidirectional ablation catheter (Blazer, Boston Scientific). All patients underwent a combined wide area circumferential ablation and segmental pulmonary vein (PV) isolation using a circular mapping catheter and cavotricuspid isthmus ablation for right atrial flutter. The procedural end point was PV entrance block. There was no difference in atrial size, left ventricular systolic function, or type of AF between groups. PV entrance block was achieved in all patients. Mean procedure time was 279 +/- 60 minutes in the conventional group versus 209 +/- 56 minutes in the RMN group (p <0.001). Mean fluoroscopy time in the conventional group was 58.6 +/- 21 minutes versus 19.5 +/- 9.8 in the RMN group (p <0.001). At 1 year there were 15 patients in the conventional group and 16 in the RMN group free from clinical AF and off antiarrhythmic drugs (p = NS). There were 2 additional ablations performed for atypical atrial flutter in the conventional group and 3 in the RMN group (p = ns). Ablation catheter char formation was not observed. There were no procedural complications. In conclusion, radiofrequency ablation of AF performed with RMN is safe and feasible. Compared with conventional hand-navigated ablation, RMN ablation results in similar clinical outcomes with decreased fluoroscopy and procedure times.

Failure of impedance monitoring to prevent adverse clinical events caused by fracture of a recalled high-voltage implantable cardioverter-defibrillator lead.

BACKGROUND: The Medtronic Sprint Fidelis implantable cardioverter-defibrillator high-voltage lead is prone to fracture. The October 2007 safety advisory recommended lead impedance monitoring to aid in identifying lead fractures. OBJECTIVE: The aim of this single-center study was to examine the effectiveness of impedance monitoring for detecting Sprint Fidelis lead failures before they caused adverse clinical events such as inappropriate shocks. METHODS: Impedance and sensing information were acquired during routine clinic and CareLink follow-up and at the time of lead failure using the Patient Alert, sensing integrity counter, nonsustained episode, and electrogram features in Medtronic pulse generators. RESULTS: Between September 2004 and February 2008, 17 of 514 Sprint Fidelis leads (3.3%) followed up at our center failed between 11 and 35 months after implantation (mean 23.0 +/- 8.0 months). Fifteen of these failures (88%) were caused by pace-sense conductor fractures, and 2 (12%) were caused by high-voltage conductor defects. Twelve of 15 patients (80%) with pace-sense conductor fractures received inappropriate shocks; of these, 4 had no significant increase in lead impedance before they were shocked, 2 were shocked <3 hours after their lead impedances exceeded the 1,000 Omega audible alert threshold, and 2 patients did not hear the alarm. All pace-sense conductor failures whose sensing function could be evaluated (13 of 15) had oversensing based on stored data, and oversensing usually (11 of 13) preceded impedances changes. CONCLUSION: Impedance monitoring did not prevent inappropriate shocks in two-thirds of our patients. Thus, pace-sense conductor impedance monitoring as currently implemented does not reliably forewarn patients of a lead malfunction. Consequently, patients who have Sprint Fidelis leads remain at risk for adverse clinical events associated with pace-sense conductor fracture.

Early failure of a small-diameter high-voltage implantable cardioverter-defibrillator lead.

BACKGROUND: We have observed a higher than expected rate of Sprint Fidelis model 6949 lead failures in our practice. OBJECTIVE: The aim of this study was to assess the performance of small-diameter Sprint Fidelis high-voltage ICD leads. METHODS: The actuarial survival of Sprint Fidelis model 6949 leads implanted at our center was compared with that of the Sprint Quattro Secure model 6947. The United States Food and Drug Administration Manufacturers and User Facility Device Experience (MAUDE) database was searched for Sprint Fidelis models. RESULTS: The survival of 583 Sprint Fidelis 6949 leads implanted at our center between September 2004 and February 2007 was significantly less than 285 Sprint Quattro Secure model 6947 leads implanted by us between November 2001 and February 2007 (P = .005). Six patients presented with Sprint Fidelis lead failure 4-23 months after implant. Five of the six patients experienced multiple inappropriate shocks associated with pace-sense conductor and coil fractures; the sixth patient had a fixation mechanism failure. The MAUDE search rendered reports for 679 Sprint Fidelis leads. The most frequent complaints or observations were inappropriate shocks (33%), high impedance (33%), and fracture (35%). Of 125 leads analyzed by the manufacturer, 62 involved fracture of the pace-sense conductor or coil and the high-voltage (defibrillation) conductor. CONCLUSIONS: The Sprint Fidelis high-voltage lead appears to be prone to early failure. Its use should be limited until the failure mechanism is identified and corrected. Patients should be evaluated quarterly, and automatic lead test features should be enabled. While more data are needed, routine prophylactic replacement of intact, normally functioning Sprint Fidelis leads does not appear justified.

Implantable cardioverter-defibrillator therapy improves long-term survival in patients with unexplained syncope, cardiomyopathy, and a negative electrophysiologic study.

OBJECTIVES: The purpose of this study was to evaluate the long-term outcomes of patients with unexplained syncope, ischemic or nonischemic cardiomyopathy, and a negative electrophysiologic study (EPS). BACKGROUND: EPS is frequently performed to evaluate syncope in patients with left ventricular dysfunction. Limited long-term data evaluating all-cause mortality in patients with no inducible arrhythmia or examining the potential benefits from implantable cardioverter-defibrillator (ICD) therapy are available. METHODS: We evaluated 102 consecutive patients with unexplained syncope, cardiomyopathy, and a negative EPS from September 1996 to December 2000. A blinded matched case-control analysis utilized 51 of these patients (19 treated with an ICD and 32 matched controls treated with conventional therapy). We compared primary endpoint of death and documented cardiac arrest of patients treated with ICD therapy to matched controls. RESULTS: Baseline characteristics were similar between groups. There were 14 primary events among the study population during a follow-up period of 44.3 +/- 20 months: 2 in the ICD group and 12 in the conventional therapy group. The hazard ratio for the risk of event in the ICD group compared with the conventional therapy group was 0.18 (95% confidence interval, 0.04-0.85; P = .04). Other comorbid conditions, including age, sex, ischemic etiology of heart failure, ejection fraction, and antiarrhythmic use, did not predict outcome. Appropriate ICD shocks occurred in 26% of patients at 2 years. CONCLUSIONS: This study suggests that empiric ICD therapy improves long-term outcomes in patients with unexplained syncope, ischemic or nonischemic cardiomyopathy, and negative EPS.

Simplified peak power reserve in patients with an implantable cardioverter-defibrillator and advanced heart failure.

The prognostic ability of simplified peak power (SPP) reserve, a novel measure of left ventricular systolic performance, was prospectively studied in patients with advanced heart failure (HF) and implantable cardioverter-defibrillators. Reduced SPP reserve identified patients who are at high risk for experiencing progressive HF.

Aortocoronary dissection complicating a percutaneous coronary intervention.

Aortocoronary dissection complicating diagnostic angiography or percutaneous coronary intervention is a rare occurrence. We present a case of aortocoronary dissection complicating a right coronary artery intervention. After closing the entry port with intracoronary stenting, the patient was managed conservatively. Serial computed tomography scans demonstrated spontaneous resolution of the dissection.