Inappropriate defibrillator shocks from depolarization--repolarization mismatch in a patient with hypertrophy cardiomyopathy

Despite wide use of dedicated bipolar sensing electrodes in implantable cardioverter-defibrillator (ICD) systems, oversensing occasionally occurs, leading to unwarranted shocks or antitachycardia pacing. This case report highlights an individual with hypertrophic cardiomyopathy (HCM) who experienced inappropriate shocks from oversensing of repolarization electrograms (T-waves). During the implantation procedure, no excessive T-wave amplitudes were detected during sinus rhythm, ventricular pacing, or induced ventricular fibrillation. T-wave oversensing leading to shocks only developed after maturation of the lead-tissue interface. An adequate safety margin for discrimination between ventricular electrograms and T-waves could not be assured. Thus, insertion of a new dedicated pacing-sensing electrode was required. The degree to which intracardiac repolarization signals may be heightened in patients with HCM has not been investigated systematically. However, a relative decrease in the ventricular electrogram amplitude without a concomitant decline of the intracardiac T-wave amplitude appears to have led to the problem in this patient. Special caution in technique and device selection with a particular emphasis on T-wave sensing may be prudent when ICDs are implanted in individuals with HCM. Additional programmable variables may also be beneficial in such cases.     

Etoposide causes illegitimate V(D)J recombination in human lymphoid leukemic cells

Etoposide is one of the most widely used antineoplastics. Unfortunately, the same treatment schedules associated with impressive efficacy are associated with an increased risk of secondary acute myeloid leukemia (AML), which has prompted its withdrawal from some treatment regimens, thereby potentially compromising efficacy against the original tumor. Because etoposide-associated AML is characterized by site-specific illegitimate DNA recombination, we studied whether etoposide could directly cause site-specific deletions of exons 2 and 3 in the hprt gene. Human lymphoid CCRF-CEM cells were treated with etoposide for 4 hours, and DNA was isolated after subculturing. The deletion of exons 2 and 3 from hprt was assayed by a quantitative polymerase chain reaction (PCR) method. In the absence of etoposide treatment, the frequency of deletions of exons 2 and 3 was very low (5.05 x 10(-8)). After exposure to 10 mumol/ L etoposide, the frequency of the exon 2 + 3 deletion was increased immediately after and at 24 hours after etoposide treatment (65 to 89 x 10(-8)) and increased to higher levels (128 to 173 x 10(-8)) after 2 and 6 days of subculture (P < .001 overall). The frequency of the exon 2 + 3 deletion assessed at 6 days of subculture after 4 hours of 0, 0.25, 1, 2.5, 5, and 10 mumol/L etoposide treatment increased with etoposide concentration, ie, 5.05 x 10(-8), 89.2 x 10(-8), 108 x 10(-8), 142 x 10(-8), 163 x 10(-8), and 173 x 10(-8), respectively (P < .0001). Sequencing of a subset of amplified products confirmed the presence of DNA sequences at the breakpoints consistent with V(D)J recombination. By contrast, exon 2 + 3 deletions after etoposide treatment in the myeloid cell lines KG-1A and K562 showed no evidence of V(D)J recombinase in their genesis. We conclude that etoposide can induce the illegitimate site-specific action of V(D)J recombinase on an unnatural DNA substrate after a single treatment in human lymphoid cells.