Non-contrast MR angiography of pelvic arterial vasculature using the Quiescent interval slice selective (QISS) sequence.

To evaluate Quiescent Interval Slice Selective (QISS) balanced steady-state free precession (bSSFP) and QISS fast low-angle shot (FLASH) sequences for non-contrast Magnetic Resonance Angiography (MRA) of iliac arteries regarding image quality and diagnostic confidence in order to establish these sequences in daily clinical practice. A prospective study of healthy subjects (n = 10) was performed. All subjects underwent the QISS MRI protocol with bSSFP und FLASH sequences. Vessel contrast-to-background ratio (VCBR) were measured in pre-defined vessel segments. Image quality and diagnostic confidence was assessed using a Likert scale (five-point scale). Inter-reader agreement was determined using Cohen's kappa coefficient (κ). Ten healthy subjects (median age 29 years, IQR: 26.25 to 30 years) were included in this prospective study. Median MR examination time was 2:05 min (IQR 1:58 to 2:16) for QISS bSSFP and 4:11 min (IQR 3:57 to 4:32) for QISS FLASH. Both sequences revealed good VCBR in all examined vessel segments. VCBR (muscle tissue) were marginally higher for FLASH sequences (e.g., 0.82 vs. 0.78 in the right femoral artery, p = 0.035*), while bSSFP sequence showed significantly higher VCBR (fat tissue) in the majority of examined arterials vessels (e.g., 0.78 vs. 0.62 in right femoral artery, p = 0.001*). The image quality and diagnostic confidence of both sequences were rated as good to excellent. Moderate to good inter-reader agreement was found. QISS MRA using bSSFP and FLASH sequences are diagnostic for visualization of iliac arterial vasculature. The QISS bSSFP sequence might offer advantages due to the markedly shorter exam time and superior visualization of smaller vessels. The QISS FLASH sequence seems to be a robust alternative for non-contrast MRA since it is less sensitive to magnetic field inhomogeneities.

Distress-Mediated Remodeling of Cardiac Connexin-43 in a Novel Cell Model for Arrhythmogenic Heart Diseases.

Gap junctions and their expression pattern are essential to robust function of intercellular communication and electrical propagation in cardiomyocytes. In healthy myocytes, the main cardiac gap junction protein connexin-43 (Cx43) is located at the intercalated disc providing a clear direction of signal spreading across the cardiac tissue. Dislocation of Cx43 to lateral membranes has been detected in numerous cardiac diseases leading to slowed conduction and high propensity for the development of arrhythmias. At the cellular level, arrhythmogenic diseases are associated with elevated levels of oxidative distress and gap junction remodeling affecting especially the amount and sarcolemmal distribution of Cx43 expression. So far, a mechanistic link between sustained oxidative distress and altered Cx43 expression has not yet been identified. Here, we propose a novel cell model based on murine induced-pluripotent stem cell-derived cardiomyocytes to investigate subcellular signaling pathways linking cardiomyocyte distress with gap junction remodeling. We tested the new hypothesis that chronic distress, induced by rapid pacing, leads to increased reactive oxygen species, which promotes expression of a micro-RNA, miR-1, specific for the control of Cx43. Our data demonstrate that Cx43 expression is highly sensitive to oxidative distress, leading to reduced expression. This effect can be efficiently prevented by the glutathione peroxidase mimetic ebselen. Moreover, Cx43 expression is tightly regulated by miR-1, which is activated by tachypacing-induced oxidative distress. In light of the high arrhythmogenic potential of altered Cx43 expression, we propose miR-1 as a novel target for pharmacological interventions to prevent the maladaptive remodeling processes during chronic distress in the heart.

Improving electrical properties of iPSC-cardiomyocytes by enhancing Cx43 expression.

The therapeutic potential of induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) is limited by immature functional features including low impulse propagation and reduced cell excitability. Key players regulating electrical activity are voltage-gated Na+ channels (Nav1.5) and gap junctions built from connexin-43 (Cx43). Here we tested the hypothesis that enhanced Cx43 expression increases intercellular coupling and influences excitability by modulating Nav1.5. Using transgenic approaches, Cx43 and Nav1.5 localization and cell coupling were studied by confocal imaging. Nav1.5 currents and action potentials (APs) were measured using the patch-clamp technique. Enhanced sarcolemmal Cx43 expression significantly improved intercellular coupling and accelerated dye transfer kinetics. Furthermore, Cx43 modulated Nav1.5 function leading to significantly higher current and enhanced AP upstroke velocities, thereby improving electrical activity as measured by microelectrode arrays. These findings suggest a mechanistic link between cell coupling and excitability controlled by Cx43 expression in iPSC-CMs. Therefore, we propose Cx43 as novel molecular target for improving electrical properties of iPSC-CMs to match the functional properties of native myocytes.