Ventricular Tachyarrhythmias in Patients With Hypertrophic Cardiomyopathy and Defibrillators: Triggers, Treatment, and Implications.

INTRODUCTION: Triggers and ICD interventions of ventricular arrhythmias in patients with hypertrophic cardiomyopathy (HCM) offer insight into mechanisms and treatment. METHODS AND RESULTS: Intracardiac ICD electrograms from 71 HCM patients in the HCM I and II studies were analyzed by three individuals. Rhythms were defined as VF (polymorphic ventricular arrhythmia), VT (monomorphic ventricular tachycardia), and ventricular flutter (VFL; VT ≥ 240 bpm). Physical activity and rhythm preceding the arrhythmia were ascertained. Of 149 arrhythmias, VF was present in 74, VT in 57, and VFL in 18. In those whose activity was known, moderate or intense physical activity was associated with over 50% of the tachycardias (57 of 111). Rhythms preceding ventricular arrhythmias were often sinus tachycardia (49 of 149; 33%) or rapid atrial fibrillation (7 of 149; 5%). VF and VFL were more likely preceded by supraventricular rhythms >100 bpm (30 of 68 with VF; 44%; 12 of 16 with VFL 75%, vs. 14 of 50 with VT 28%; P = 0.001). Antitachycardia pacing (ATP) was successful in 39 of 53 (74%). Multiple shocks were more often required to terminate VFL (10 of 18; 56%) compared to VF (10 of 72; 14%) and VT (2 of 25; 8%; P < 0.0001). Of arrhythmias requiring more than one shock to terminate, 16 of 22 were preceded by sinus tachycardia and/or moderate or extreme physical activity. CONCLUSIONS: Rapid supraventricular rhythms, and at least moderate activity, frequently precede VT and VF, and when they occur in these situations often require multiple ICD shocks to restore sinus rhythm. ATP is successful in terminating VT and VFL, and should be a programmed in all HCM patients with ICDs.

A primer on arrhythmias in patients with hypertrophic cardiomyopathy.

Patients with hypertrophic cardiomyopathy are at risk of atrial and ventricular arrhythmias, yet treatment options for these patients are made almost solely by extrapolation from patients with other diseases. Heart block may be seen spontaneously but is especially prevalent following septal reduction strategies. Atrial fibrillation is the most common arrhythmia in patients with hypertrophic cardiomyopathy. The onset of atrial fibrillation often represents a turning point clinically for patients, marked by substantial functional deterioration and morbidity. Sudden cardiac death is the most common cause of death in the young patient, but still contributes to mortality in older patients. Major risk factors for sudden cardiac death include resuscitated sudden cardiac death, marked hypertrophy, syncope, and family history of sudden cardiac death due to hypertrophic cardiomyopathy. Minor risk factors for sudden cardiac death include nonsustained ventricular tachycardia, and hypotensive response to exercise. Emerging possible risk factors include atrial fibrillation, myocardial ischemia, left ventricular outflow tract obstruction, genetic mutations, left ventricular apical aneurysms, myocardial fibrosis, and end stage disease.

Contact-force radiofrequency ablation of non-paroxysmal atrial fibrillation: improved outcomes with increased experience.

INTRODUCTION: Clinical trials have failed to reliably show improved outcomes with utilization of contact-force sensing (CFS) radiofrequency (RF) ablation catheters. It is unknown whether the unfavorable outcomes observed in these trials are attributable to inexperience with CFS technology. OBJECTIVES: To compare catheter ablation outcomes of stepwise linear ablation with versus without CFS technology and to assess the impact of operator experience with CFS technology on procedural outcomes. METHODS: Clinical outcomes were evaluated in 228 consecutive NPAF patients undergoing first-time left atrial ablation using a stepwise linear approach. Arrhythmia recurrence was assessed using 2-week event monitors at 3-month intervals following index ablation. RESULTS: A total of 228 patients were included in our study. There was no statistically significant difference in risk of recurrent atrial arrhythmias at 12 and 24 months between CFS and non-CFS patients (p = 0.5 and p = 0.169). The time to recurrence of atrial arrhythmias at 24 months in the second half of CFS patients was significantly lower when compared to both the first half of CFS patients (p = 0.002) and non-CFS patients (p = 0.005). CONCLUSION: While there was no difference in overall outcomes between CFS and non-CFS ablation using a stepwise linear approach in patients with NPAF, procedural efficacy of the second half of CFS patients was significantly improved compared to both the first half of CFS patients and all non-CFS patients. Lack of benefit seen in clinical trials using CFS technology may be related to operator inexperience with CFS ablation catheters at the time of the trials.

Identification of the nuclear localization and export signals of high risk HPV16 E7 oncoprotein.

The E7 oncoprotein of high risk human papillomavirus type 16 (HPV16) binds and inactivates the retinoblastoma (RB) family of proteins. Our previous studies suggested that HPV16 E7 enters the nucleus via a novel Ran-dependent pathway independent of the nuclear import receptors (Angeline, M., Merle, E., and Moroianu, J. (2003). The E7 oncoprotein of high-risk human papillomavirus type 16 enters the nucleus via a nonclassical Ran-dependent pathway. Virology 317(1), 13-23.). Here, analysis of the localization of specific E7 mutants revealed that the nuclear localization of E7 is independent of its interaction with pRB or of its phosphorylation by CKII. Fluorescence microscopy analysis of enhanced green fluorescent protein (EGFP) and 2xEGFP fusions with E7 and E7 domains in HeLa cells revealed that E7 contains a novel nuclear localization signal (NLS) in the N-terminal domain (aa 1-37). Interestingly, treatment of transfected HeLa cells with two specific nuclear export inhibitors, Leptomycin B and ratjadone, changed the localization of 2xEGFP-E7(38-98) from cytoplasmic to mostly nuclear. These data suggest the presence of a leucine-rich nuclear export signal (NES) and a second NLS in the C-terminal domain of E7 (aa 38-98). Mutagenesis of critical amino acids in the putative NES sequence ((76)IRTLEDLLM(84)) changed the localization of 2xEGFP-E7(38-98) from cytoplasmic to mostly nuclear suggesting that this is a functional NES. The presence of both NLSs and an NES suggests that HPV16 E7 shuttles between the cytoplasm and nucleus which is consistent with E7 having functions in both of these cell compartments.