Differential binding of ligands to the apolipoprotein E receptor 2

Apolipoprotein E receptor 2 (apoER2) is an important participant in the Reelin signaling pathway that directs cell positioning during embryogenesis. ApoER2 is a cell surface molecule that elicits intracellular signal transduction through binding of Reelin. The structural requirements for Reelin binding to apoER2 and the receptor domains involved in this process are unclear at present. Using a series of receptor mutants, we characterized the interaction of apoER2 with Reelin and compared this interaction to that of apoER2 with the receptor-associated protein (RAP), an apoER2 ligand that does not induce signaling. By surface plasmon resonance we demonstrate that apoER2 exhibits 6-fold higher affinity for Reelin than the very low density lipoprotein receptor (VLDLR), which also functions as a Reelin receptor (KD 0.2 nM versus KD 1.2 nM). Acidic amino acid residues in complement-type repeat domains 1 and 3 of apoER2 are required for Reelin binding. The same regions of the receptor are also bound by RAP with a 25-fold lower affinity (KD 5 nM). Whereas RAP binds to apoER2 with a 1:1 stoichiometry, experimental evidence suggests that Reelin associates with two or more receptor molecules simultaneously to achieve high-affinity interaction. This finding indicates that aggregation of apoER2 by multivalent ligands such as Reelin may be the structural basis for signal transduction

Prevalence and prognostic value of left ventricular late gadolinium enhancement in patients with idiopathic outflow tract ventricular arrhythmias

Abstract Background Patients with idiopathic outflow tract ventricular arrhythmias (OTVAs) and structurally normal heart by ECG and echocardiogram often undergo cardiac magnetic resonance (CMR) study to evaluate for presence of concealed myocardial abnormalities with late gadolinium enhancement (LGE). However, the clinical impact of incidental LGE finding in the left ventricle (LV) in patients with idiopathic OT-VAs is unclear. Accordingly, the aim of the present study was to investigate the prevalence, characteristics and prognostic significance of isolated LV LGE in a large population of patients with OTVA undergoing CMR. Methods A total of 364 consecutive patients (43±16 years, 53% male) with OTVA and negative routine diagnostic work-up were included. All patients underwent a CMR study with LGE imaging for detection of scar/replacement fibrosis. Presence of LGE was correlated with long term major adverse cardiovascular events including sudden cardiac death (SCD), resuscitated cardiac arrest and nonfatal documented sustained ventricular tachycardia. Results Isolated LGE in the LV was identified in 15 patients (4%), typically involving the inferolateral wall (11 cases, 73%) and having a median extension of 3 (2–5)% of the LV mass. All cases showed a midmyocardial/subepicardial distribution consistent with a possible prior myocarditis. Patients with incidental finding of LV-LGE were older (55±13 years vs. 42±16 years; p&amp;lt;0.01) and were more frequently males (80% vs. 51%; p=0.03). After a median follow-up of 69 (47–98) months, none of the patients in the LV-LGE group and 1 patient (0.3%) in the non-LGE group (p=1.0) experienced the composite end-point which consisted in an episode of sustained VT with hypotension and dizziness. The patient subsequently underwent effective radiofrequency ablation of the VT from the right ventricular outflow tract. Conclusion In this large CMR study, isolated LV scar was found in 4% of patients with idiopathic OT-VAs, was small in size with distribution consistent with prior myocarditis. The LGE abnormality did not portend a negative prognosis. Funding Acknowledgement Type of funding source: None </jats:sec

Prognostic value of non-ischemic ring-like left ventricular scar pattern in patients with apparently idiopathic ventricular arrhythmias: a CMR imaging study

Abstract Background The presence of left ventricular (LV) late gadolinium enhancement (LGE) at cardiac magnetic resonance (CMR) has been correlated to life-threatening arrhythmic events in patients with apparently idiopathic ventricular arrhythmias (VAs). Aim of the present study was to investigate the prognostic significance of a specific LV-LGE phenotype characterized by a subepicardial/midmyocardial “ring-like” pattern of fibrosis. Methods Out of a total of 518 consecutive patients with apparently idiopathic VAs who underwent CMR study, 79 (15%) had evidence of LV-LGE. Of these, 23 (4%) patients had LV LGE with ring-like pattern, defined as subepicardial or midmyocardial LGE involving at least 3 contiguous segments in the same slice (group A), while 56 (11%) patients had LV LGE with no ring-like pattern (group B). The remaining 439 patients had no LGE (group C). The end-point of the study was a composite SCD, resuscitated cardiac arrest and nonfatal episodes of ventricular fibrillation or documented sustained ventricular tachycardia. Results Group A patients were more frequently males compared to groups B and C (96% vs. 79% vs. 52%; p&amp;lt;0.01) and had more frequently a family history of SCD and/or cardiomyopathy (30% vs. 11% vs. 5%; p&amp;lt;0.01). All patients in Group A showed VAs with a predominant RBBB morphology vs. 38 (68%) patients in Group B and 65 (15%) in Group C (p&amp;lt;0.01). During a follow-up of 63±39 months, the composite outcome occurred in 13 patients (57%) in Group A vs. 11 (20%) in Group B and 2 (1%) in Group C (p&amp;lt;0.01). Conclusion In patients with apparently idiopathic VAs, a nonischemic LV-LGE with a ring-like pattern at CMR is associated with a high rate of malignant arrhythmic events during follow-up. Funding Acknowledgement Type of funding source: None </jats:sec

Prognostic Value of Nonischemic Ringlike Left Ventricular Scar in Patients with Apparently Idiopathic Nonsustained Ventricular Arrhythmias

none24Background: Left ventricular (LV) scar on late gadolinium enhancement (LGE) cardiac magnetic resonance has been correlated with life-threatening arrhythmic events in patients with apparently idiopathic ventricular arrhythmias (VAs). We investigated the prognostic significance of a specific LV-LGE phenotype characterized by a ringlike pattern of fibrosis. Methods: A total of 686 patients with apparently idiopathic nonsustained VA underwent contrast-enhanced cardiac magnetic resonance. A ringlike pattern of LV scar was defined as LV subepicardial/midmyocardial LGE involving at least 3 contiguous segments in the same short-axis slice. The end point of the study was time to the composite outcome of all-cause death, resuscitated cardiac arrest because of ventricular fibrillation or hemodynamically unstable ventricular tachycardia and appropriate implantable cardioverter defibrillator therapy. Results: A total of 28 patients (4%) had a ringlike pattern of scar (group A), 78 (11%) had a non-ringlike pattern (group B), and 580 (85%) had normal cardiac magnetic resonance with no LGE (group C). Group A patients were younger compared with groups B and C (median age, 40 vs 52 vs 45 years; P&lt;0.01), more frequently men (96% vs 82% vs 55%; P&lt;0.01), with a higher prevalence of family history of sudden cardiac death or cardiomyopathy (39% vs 14% vs 6%; P&lt;0.01) and more frequent history of unexplained syncope (18% vs 9% vs 3%; P&lt;0.01). All patients in group A showed VA with a right bundle-branch block morphology versus 69% in group B and 21% in group C (P&lt;0.01). Multifocal VAs were observed in 46% of group A patients compared with 26% of group B and 4% of group C (P&lt;0.01). After a median follow-up of 61 months (range, 34-84 months), the composite outcome occurred in 14 patients (50.0%) in group A versus 15 (19.0%) in group B and 2 (0.3%) in group C (P&lt;0.01). After multivariable adjustment, the presence of LGE with ringlike pattern remained independently associated with increased risk of the composite end point (hazard ratio, 68.98 [95% CI, 14.67-324.39], P&lt;0.01). Conclusions: In patients with apparently idiopathic nonsustained VA, nonischemic LV scar with a ringlike pattern is associated with malignant arrhythmic events.noneMuser D.; Nucifora G.; Muser D.; Nucifora G.; Pieroni M.; Castro S.A.; Casado Arroyo R.; Maeda S.; Benhayon D.A.; Liuba I.; Sadek M.; Magnani S.; Enriquez A.; Liang J.J.; Sassone B.; Desjardins B.; Dixit S.; Deo R.; Garcia F.C.; Callans D.J.; Frankel D.S.; Selvanayagam J.B.; Marchlinski F.E.; Santangeli P.Muser, D.; Nucifora, G.; Muser, D.; Nucifora, G.; Pieroni, M.; Castro, S. A.; Casado Arroyo, R.; Maeda, S.; Benhayon, D. A.; Liuba, I.; Sadek, M.; Magnani, S.; Enriquez, A.; Liang, J. J.; Sassone, B.; Desjardins, B.; Dixit, S.; Deo, R.; Garcia, F. C.; Callans, D. J.; Frankel, D. S.; Selvanayagam, J. B.; Marchlinski, F. E.; Santangeli, P