Is abnormal myocardial repolarization associated with the occurrence of malignant tachyarrhythmias in Takotsubo cardiomyopathy?

Background: Abnormalities of cardiac repolarization are a hallmark of Takotsubo cardiomyopathy (TC), but their association with the occurrence of syncope and ventricular tachyarrhythmias is unknown. This study sought to assess the relationship between myocardial repolarization and malignant tachyarrhythmias in TC.Methods: Clinical data and electrocardiographic repolarization parameters of 28 patients with TC and ventricular tachyarrhythmias (n = 26) or syncope (n = 2) were compared to data from 20 randomly selected patients with TC but without ventricular tachyarrhythmias or syncope.Results: Study patients had signifi cantly lower ejection fraction (EF) compared with controls (35 ± 14% vs. 46 ± 10%, p = 0.006). On day 1, no signifi cant differences in repolarization parameters were observed. However, in the subgroup with ventricular fi brillation ([VF]; n = 10), Tpeak-Tend in lead V6 was significantly prolonged (97 ± 20 vs. 85 ± 19 ms; p = 0.04). Similarly, in the subgroup with torsade de pointes ([TdP]; n = 5) Tpeak-Tend in lead V4 wasprolonged (127 ± 21 vs. 94 ± 27 ms; p = 0.001). On day 3, Tpeak-Tend in lead V3 (130 ± 51 vs. 105 ± 21 ms, p = 0.049) and Tpeak-Tend dispersion (56 ± 33 vs. 36 ± 21 ms; p = 0.03) were signifi cantly longer in study patients. The difference in Tpeak-Tend in lead V3 was borderline in the VF subgroup, but significant in the subgroup with TdP. The latter grouphad also longer Tpeak-Tend in lead V4 and longer corrected QT interval in leads V3 and V4.Conclusions: Patients with TC who experience malignant tachyarrhythmias have lower EF and a more pronounced alteration of the spatial dispersion of ventricular repolarization

Advances for Treating in-Hospital Cardiac Arrest: Safety and Effectiveness of a New Automatic External Cardioverter-Defibrillator

OBJECTIVES: The purpose of this study was to prospectively analyze the performance and safety of a new programmable, fully automatic external cardioverter-defibrillator (AECD) in a European multicenter trial. BACKGROUND Although, the response time to cardiac arrest (CA) is a major determinant of mortality and morbidity, in-hospital strategies have not significantly changed during the last 30 years. METHODS: Patients (n = 117) at risk of CA in monitored wards (n = 51) and patients undergoing electrophysiologic testing or implantable cardioverter-defibrillator (ICD) implantation (n = 66) were enrolled. The accuracy of the automatic response of the device to any change of rhythm (lasting >1 s and >4 beats) was confirmed by reviewing the simultaneously recorded Holter data and the programmed parameters. RESULTS: During 1,240 h, 1,988 episodes of rhythm changes were documented. A total of 115 episodes lasted > or =10 s or needed treatment (pacing, n = 32; ICD, n = 51; AECD, n = 35) for termination. The device detected ventricular tachyarrhythmias with a sensitivity of 100% and specificity of 97.6% (true negatives, n = 1,454; true positives, n = 499; false positives, n = 35; false negatives, n = 0). The false positives were all caused by T-wave oversensing during ventricular pacing. There were no complications or adverse events. The mean response time was 14.4 s for those episodes needing a full charge of the capacitor. CONCLUSIONS: This new AECD is safe and effective in detecting, monitoring, and treating spontaneous arrhythmias. This fully automatic device shortens the response time to treatment, and it is likely that it will significantly improve the outcome of patients with in-hospital CA

Randomized, double blind study of non-excitatory, cardiac contractility modulation electrical impulses fr symptomatic heart failure

AIMS: We performed a randomized, double blind, crossover study of cardiac contractility modulation (CCM) signals in heart failure patients. METHODS AND RESULTS: One hundred and sixty-four subjects with ejection fraction (EF) < 35% and NYHA Class II (24%) or III (76%) symptoms received a CCM pulse generator. Patients were randomly assigned to Group 1 (n = 80, CCM treatment 3 months, sham treatment second 3 months) or Group 2 (n = 84, sham treatment 3 months, CCM treatment second 3 months). The co-primary endpoints were changes in peak oxygen consumption (VO2,peak) and Minnesota Living with Heart Failure Questionnaire (MLWHFQ). Baseline EF (29.3 +/- 6.7% vs. 29.8 +/- 7.8%), VO2,peak (14.1 +/- 3.0 vs. 13.6 +/- 2.7 mL/kg/min), and MLWHFQ (38.9 +/- 27.4 vs. 36.5 +/- 27.1) were similar between the groups. VO2,peak increased similarly in both groups during the first 3 months (0.40 +/- 3.0 vs. 0.37 +/- 3.3 mL/kg/min, placebo effect). During the next 3 months, VO2,peak decreased in the group switched to sham (-0.86 +/- 3.06 mL/kg/min) and increased in patients switched to active treatment (0.16 +/- 2.50 mL/kg/min). MLWHFQ trended better with treatment (-12.06 +/- 15.33 vs. -9.70 +/- 16.71) during the first 3 months, increased during the second 3 months in the group switched to sham (+4.70 +/- 16.57), and decreased further in patients switched to active treatment (-0.70 +/- 15.13). A comparison of values at the end of active treatment periods vs. end of sham treatment periods indicates statistically significantly improved VO2,peak and MLWHFQ (P = 0.03 for each parameter). CONCLUSION: In patients with heart failure and left ventricular dysfunction, CCM signals appear safe; exercise tolerance and quality of life (MLWHFQ) were significantly better while patients were receiving active treatment with CCM for a 3-month period

Studying Brugada syndrome with an SCN1B variants in human-induced pluripotent stem cell-derived cardiomyocytes

BACKGROUND: Among rare channelopathies BrS patients are at high risk of sudden cardiac death (SCD). SCN5A mutations are found in a quarter of patients. Other rare gene mutations including SCN1B have been implicated to BrS. Studying the human cellular phenotype of BrS associated with rare gene mutation remains lacking. OBJECTIVES: We sought to study the cellular phenotype of BrS with the SCN1B gene variants using human-induced pluripotent stem cell (hiPSCs)–derived cardiomyocytes (hiPSC-CMs). METHODS AND RESULTS: A BrS patient suffering from recurrent syncope harboring a two variants (c.629T > C and c.637C > A) in SCN1B, which encodes the function-modifying sodium channel beta1 subunit, and three independent healthy subjects were recruited and their skin biopsies were used to generate hiPSCs, which were differentiated into cardiomyocytes (hiPSC-CMs) for studying the cellular electrophysiology. A significantly reduced peak and late sodium channel current (I(Na)) and a shift of activation curve to more positive potential as well as a shift of inactivation curve to more negative potential were detected in hiPSC-CMs of the BrS patient, indicating that the SCN1B variants impact the function of sodium channels in cardiomyocytes. The reduced I(Na) led to a reduction of amplitude (APA) and upstroke velocity (V(max)) of action potentials. Ajmaline, a sodium channel blocker, showed a stronger effect on APA and Vmax in BrS cells as compared to cells from healthy donors. Furthermore, carbachol was able to increase arrhythmia events and the beating frequency in BrS. CONCLUSION: Our hiPSC-CMs from a BrS-patient with two variants in SCN1B recapitulated some key phenotypic features of BrS and can provide a platform for studies on BrS with SCN1B variants

Heterodimerization of AML1/ETO with CBFβ is required for leukemogenesis but not for myeloproliferation

The AML1/Runx1 transcription factor and its heterodimerization partner CBFβ are essential regulators of myeloid differentiation. The chromosomal translocation t(8;21), fusing the DNA binding domain of AML1 to the corepressor eight-twenty-one (ETO), is frequently associated with acute myeloid leukemia and generates the AML1/ETO (AE) fusion protein. AE represses target genes usually activated by AML1 and also affects the endogenous repressive function of ETO at Notch target genes. In order to analyze the contribution of CBFβ in AE-mediated leukemogenesis and deregulation of Notch target genes, we introduced two point mutations in a leukemia-initiating version of AE in mice, called AE9a, that disrupt the AML1/CBFβ interaction (AE9aNT). We report that the AE9a/CBFβ interaction is not required for the AE9a-mediated aberrant expression of AML1 target genes, while upregulation/derepression of Notch target genes does require the interaction with CBFβ. Using retroviral transduction to express AE9a in murine adult bone marrow-derived hematopoietic progenitors, we observed that both AE9a and AE9aNT lead to increased myeloproliferation in vivo. However, both development of leukemia and long-term replating capacity are only observed with AE9a but not with AE9aNT. Thus, deregulation of both AML1 and Notch target genes is required for the development of AE9a-driven leukemia