Background Men and women with type-2 long QT syndrome (LQT2) exhibit time-dependent differences in the risk for cardiac events. We hypothesized that data regarding the location of the disease-causing mutation in the KCNH2 channel may affect gender-specific risk in LQT2 Objectives To risk stratify LQT2 patients for life-threatening cardiac events based on clinical and genetic information. Methods The risk for life-threatening cardiac events from birth through age 40 (comprising aborted cardiac arrest [ACA] or sudden cardiac death [SCD]) years was assessed among 1,166 LQT2 males (n=490) and females (n=676) by the location of the LQTS-causing mutation in the KCNH2 channel (pre-specified in the primary analysis as pore-loop vs. nonpore-loop). Results During follow-up, the cumulative probability of life-threatening cardiac events years was significantly higher among LQT2 women (26%) as compared with men (14%; p<0.001). Multivariate analysis showed that the risk for life-threatening cardiac events was not significantly different between women with and without pore-loop mutations (HR=1.20; p=0.33). In contrast, men with pore-loop mutations displayed a significant >2-fold higher risk of a first ACA or SCD as compared with those with nonpore-loop mutations (HR=2.18; p=0.01). Consistently, women experienced a high rate of life-threatening events regardless of mutation-location (pore-loop: 35%, nonpore-loop: 23%), whereas in men the rate of ACA or SCD was high among those with pore-loop mutations (28%) and relatively low among those with nonpore-loop mutations (8%). Conclusion Combined assessment of clinical and mutation-specific data can be used for improved risk stratification for life-threatening cardiac events in type-2 long QT syndrome.

Objectives This study was designed to evaluate the clinical and prognostic aspects of long QT syndrome-related cardiac events that occur in the first year of life (infancy). Background The clinical implications for patients with long QT syndrome who experience cardiac events in infancy have not been studied previously. Methods The study population of 3,323 patients with QTc ≥ 450 ms enrolled in the International LQTS Registry involved 20 patients with sudden cardiac death (SCD), 16 patients with aborted cardiac arrest (ACA), 34 patients with syncope, and 3,253 patients who were asymptomatic during the first year of life. Results The risk factors for a cardiac event among 212 patients who had an ECG recorded in the first year of life included QTc≥500ms, heart rate ≤100bpm, and female sex. ACA before age 1 year was associated with a hazard ratio of 23.4 (p<0.01) for ACA or SCD during age 1-10 years. During the 10-year follow-up after infancy, beta-blocker therapy was associated with a significant reduction in ACA/SCD only in those with a syncopal episode within 2 years before ACA/SCD, but not for those who survived ACA in infancy. Conclusions Patients with LQTS who experience ACA during the first year of life are at very high-risk for subsequent ACA or death during their next 10 years of life, and beta-blockers may not be effective in preventing fatal or near fatal cardiac events in this small but high-risk subset.

BACKGROUND Men and women with type 1 long QT syndrome (LQT1) exhibit time-dependent differences in the risk for cardiac events. OBJECTIVE We hypothesized that sex-specific risk for LQT1 is related to the location and function of the disease-causing mutation in the KCNQ1 gene. METHODS The risk for life-threatening cardiac events (comprising aborted cardiac arrest [ACA] or sudden cardiac death [SCD]) from birth through age 40 years was assessed among 1051 individuals with LQT1 (450 men and 601 women) by the location and function of the LQT1-causing mutation (prespecified as mutations in the intracellular domains linking the membrane-spanning segments [ie, S2–S3 and S4–S5 cytoplasmic loops] involved in adrenergic channel regulation vs other mutations). RESULTS Multivariate analysis showed that during childhood (age group: 0–13 years) men had >2-fold (P < .003) increased risk for ACA/SCD than did women, whereas after the onset of adolescence the risk for ACA/SCD was similar between men and women (hazard ratio = 0.89 [P = .64]). The presence of cytoplasmic-loop mutations was associated with a 2.7-fold (P < .001) increased risk for ACA/SCD among women, but it did not affect the risk among men (hazard ratio 1.37; P = .26). Time-dependent syncope was associated with a more pronounced risk-increase among men than among women (hazard ratio 4.73 [P < .001] and 2.43 [P = .02], respectively), whereas a prolonged corrected QT interval (≥500 ms) was associated with a higher risk among women than among men. CONCLUSION Our findings suggest that the combined assessment of clinical and mutation location/functional data can be used to identify sex-specific risk factors for life-threatening events for patients with LQT1.

In MADIT-CRT, active treatment with CRT-D was associated with a significant reduction in the risk of life-threatening VTEs. However, our findings suggest that CRT-D does not reduce the risk of subsequent VTEs in patients who experience a first arrhythmic event and may increase subsequent arrhythmic risk in non-LBBB patients. (Multicenter Automatic Defibrillator Implantation With Cardiac Resynchronization Therapy [MADIT-CRT]; NCT00180271).

Phthalates are ubiquitous contaminants that target the testis during in utero and postnatal development. The PI3K/Akt and nuclear factor kappa B (NF-kappaB) signaling pathways have been implicated in germ cell survival following testicular injury. Here we observe that Akt kinase activity increases in the testes of postnatal day 28 wild-type mice following exposure to 500 mg/kg mono-(2-ethylhexyl) phthalate (MEHP), and that loss of Akt1 results in the premature onset of germ cell apoptosis. To further determine the basis for this sensitivity, we investigated the potential for cross-talk between the PI3K/Akt and NF-kappaB signaling pathways. We found a twofold increase in Akt1-dependent phosphorylation of the I kappaB alpha subunit following exposure to 500 mg/kg MEHP and decreased levels of the total I kappaB alpha protein. Examination of the expression of the NF-kappaB subunits, p50 and p65, in Akt1 wild-type testes following MEHP exposure revealed a twofold increase in p50 mRNA at 6 h. Interestingly, in Akt1-deficient testes, basal expression of both the p50 and p65 subunits was elevated 1.6- and 4-fold, respectively. This was due, at least in part, to increased levels of oxidative stress as measured by both superoxide anion formation and increased expression of SMAC/DIABLO, a proapoptotic mitochondrial protein. In wild-type testes, MEHP-induced Akt1-dependent transcription of the antiapoptotic mitochondrial target gene, Bcl-xL. Together, these results indicate that Akt1 plays a role in the initial protection of germ cells following MEHP-induced germ cell apoptosis and that this response is partially mediated by cross-talk with the NF-kappaB signaling pathway and an increased sensitivity to oxidative stress.