Faculty Bibliography

NEW FINDINGS/UNASSIGNED:transient decaying phase. ABSTRACT/UNASSIGNED:leak. Overall, ivabradine had a positive inotropic effect brought about by enhanced SERCA2a activity, which might be mediated by increased phospholamban phosphorylation. The positive inotropic effect along with the lowered heart rate underlies ivabradine's therapeutic effect in heart failure. This article is protected by copyright. All rights reserved.

Background/UNASSIGNED:Men normally have shorter heart rate-corrected QT interval (QTc) than women, at least in part due to accelerating effects of testosterone on ventricular repolarization. Accumulating data suggest that androgen-deprivation therapy (ADT) used for the treatment of prostatic cancer, may increase Torsades de Pointes (TdP) risk by prolonging QTc. However, the evidence for such an association is currently limited to few case reports, in most cases deriving from the analysis of uncontrolled sources such as pharmacovigilance databases. Objective/UNASSIGNED:To better determine the clinical impact of ADT on TdP development, we examined the prevalence of this therapy in a consecutive cohort of 66 TdP patients, prospectively collected over a ~10 years period. Methods and Results/UNASSIGNED:We found and described four patients who were under ADT for prostatic cancer when TdP occurred, and in two cases degenerated to cardiac arrest. Notably, in this unselected population, ADTs unexpectedly represented the second most frequently administered QT-prolonging medication in males (4/24, 17%), after amiodarone. Moreover, in the ADT patients, a blood withdrawal was performed within 24 h from TdP/marked QTc prolongation occurrence and circulating concentration of androgens and gonadothropins were measured. As expected, all cases showed markedly reduced testosterone levels (total, free, and available). Conclusion/UNASSIGNED:We provide evidence that a significant proportion of patients developing TdP were under treatment with ADT for prostatic cancer, thus confirming the clinical relevance of previous pharmacovigilance signals. An accurate assessment of the arrhythmic risk profile should be included in the standard of care of prostatic cancer patients before starting ADT.

Background Systemic inflammation is a strong predictor of atrial fibrillation. A key role for electrical remodeling is increasingly recognized, and experimental data suggest that inflammatory cytokines can directly affect connexins resulting in gap-junction dysfunction. We hypothesized that systemic inflammation, regardless of its origin, promotes atrial electric remodeling in vivo, as a result of cytokine-mediated changes in connexin expression. Methods and Results Fifty-four patients with different inflammatory diseases and elevated C-reactive protein were prospectively enrolled, and electrocardiographic P-wave dispersion indices, cytokine levels (interleukin-6, tumor necrosis factor-α, interleukin-1, interleukin-10), and connexin expression (connexin 40, connexin 43) were measured during active disease and after reducing C-reactive protein by >75%. Moreover, peripheral blood mononuclear cells and atrial tissue specimens from an additional sample of 12 patients undergoing cardiac surgery were evaluated for atrial and circulating mRNA levels of connexins. Finally, in vitro effects of interleukin-6 on connexin expression were studied in HL-1 mouse atrial myocytes. In patients with active inflammatory diseases, P-wave dispersion indices were increased but rapidly decreased within days when C-reactive protein normalizes and interleukin-6 levels decline. In inflammatory disease patients, both P-wave dispersion indices and interleukin-6 changes were inversely associated with circulating connexin levels, and a positive correlation between connexin expression in peripheral blood mononuclear cells and atrial tissue was demonstrated. Moreover, interleukin-6 significantly reduced connexin expression in HL-1 cells. Conclusions Our data suggest that regardless of specific etiology and organ localization, systemic inflammation, via interleukin-6 elevation, rapidly induces atrial electrical remodeling by down-regulating cardiac connexins. Although transient, these changes may significantly increase the risk for atrial fibrillation and related complications during active inflammatory processes.

Cardiac K⁺-channelopathies account for a significant proportion of arrhythmias and sudden cardiac death (SCD) in subjects without structural heart disease. It is well recognized that genetic defects are key factors in many cases and in practice, the term cardiac channelopathies currently coincides with that of inherited cardiac channelopathies. However, mounting evidence demonstrate that not only genetic alterations but also autoimmune and inflammatory factors can cause cardiac K⁺-channel dysfunction and arrhythmias in the setting of a structurally normal heart. In particular, it has been demonstrated that specific autoantibodies as well as inflammatory cytokines can modulate expression and/or function of different K⁺-channels in the heart, resulting in a disruption of the cardiac action potential and arrhythmias/SCD. Awareness to the existence of these newly recognized forms is essential to identify and adequately manage affected patients. In the present review, we focus on autoimmune and inflammatory K⁺-channelopathies as a novel mechanism for cardiac arrhythmias, and analyze the recent advancements in this topic providing complementary basic, clinical and population health perspectives.

INTRODUCTION/BACKGROUND:Successful initiation of spiral wave reentry in the neonatal rat ventricular myocyte (NRVM) monolayer implicitly assumes the presence of spatial dispersion of repolarization (DR), which is difficult to quantify. We recently introduced a NRVM monolayer that utilizes anthopleurin-A to impart a prolonged plateau to the NRVM action potential. This was associated with a significant degree of spatial DR that lends itself to accurate quantification. METHODS AND RESULTS/RESULTS:(as a surrogate of DR) to induction of spiral wave reentry around a functional core versus reentry around a fixed anatomical obstacle. We show that functional reentry could be initiated by a premature stimulus acting on a substrate of spatial DR resulting in a functional line of propagation block. Subsequent wave fronts circulated around a central core of functional obstacle created by sustained depolarization from the circulating wave front. Both initiation and termination of spiral wave reentry around an anatomical obstacle consistently required participation of a region of functional propagation block. This region was similarly based on spatial DR. Spontaneous termination of spiral wave reentry also resulted from block in the functional component of the circuit obstacle, usually preceded by beat-to-beat slowing of propagation. CONCLUSIONS:The study demonstrates the critical contribution of DR to spiral wave reentry around a purely functional core as well as reentry around a fixed anatomical core.

Congenital long QT syndrome (LQTS) has been the most investigated cardiac ion channelopathy. Although congenital LQTS remains the domain of cardiologists, cardiac electrophysiologists and specialised centres, the much more frequently acquired LQTS is the domain of physicians and other members of healthcare teams required to make therapeutic decisions. This paper reviews the electrophysiological mechanisms of acquired LQTS, its ECG characteristics, clinical presentation, and management. The paper concludes with a comprehensive review of the electrophysiological mechanisms of torsade de pointes.