Impact of KChIP2 on Cardiac Electrophysiology and the Progression of Heart Failure

Electrophysiological remodeling of cardiac potassium ion channels is important in the progression of heart failure. A reduction of the transient outward potassium current (Ito) in mammalian heart failure is consistent with a reduced expression of potassium channel interacting protein 2 (KChIP2, a KV4 subunit). Approaches have been made to investigate the role of KChIP2 in shaping cardiac Ito, including the use of transgenic KChIP2 deficient mice and viral overexpression of KChIP2. The interplay between Ito and myocardial calcium handling is pivotal in the development of heart failure, and is further strengthened by the dual role of KChIP2 as a functional subunit on both KV4 and CaV1.2. Moreover, the potential arrhythmogenic consequence of reduced Ito may contribute to the high relative incidence of sudden death in the early phases of human heart failure. With this review, we offer an overview of the insights into the physiological and pathological roles of KChIP2 and we discuss the limitations of translating the molecular basis of electrophysiological remodeling from animal models of heart failure to the clinical setting

Exercise-associated sudden death in Finnish standardbred and coldblooded trotters : - a case series with pedigree analysis

Exercise-associated sudden deaths (EASDs) are deaths occurring unexpectedly during or immediately after exercise. Sudden cardiac death (SCD) is one cause of EASD. Cardiac arrhythmias caused by genetic variants have been linked to SCD in humans. We hypothesize that genetic variants may be associated with SCD in animals, including horses. Genetic variants are transmitted to offspring and their frequency might increase within a family. Therefore, the frequency of such variants might increase with the inbreeding factor. Higher inbreeding could have a negative impact on racing performance. Pedigree data and career earnings from racehorses diagnosed with SCD between 2002 and 2017 were compared using non-parametric tests with 1) control horses that died due to catastrophic musculoskeletal injuries and 2) horses that raced during the same period without reported problems. Diagnosis of SCD was based on necropsy reports, including macroscopic and microscopic examinations. Death was registered in the study period for 61 horses. Eleven of these horses were excluded due to missing autopsy reports. In 25 cases, the diagnosis remained unknown and death was possibly caused by cardiac arrhythmia, in two cases cardiac disease was identified, in seven cases a rupture of a major vessel had occurred. In addition, 16 horses died or were euthanized due to severe musculoskeletal injuries. No significant differences in inbreeding coefficients or in career earnings were found between the groups or between horses with EASD compared with other horses racing during the same period. The study provides no evidence for increased inbreeding factor in Finnish racehorses with SCD. (c) 2021 Elsevier Inc. All rights reserved.Peer reviewe

PACAP-38 and PACAP(6–38) Degranulate Rat Meningeal Mast Cells via the Orphan MrgB3-Receptor

Infusion of pituitary adenylate cyclase activating peptide-38 (PACAP-38) provokes migraine attacks in migraineurs and headache in non-migraineurs. Adverse events like long-lasting flushing and heat sensation can be terminated with oral antihistamine treatment, indicating the involvement of mast cell activation after PACAP-infusion. Degranulation of rat peritoneal mast cells was provoked by several isoforms of PACAP via previously unknown receptor pharmacology. The effect might thus be mediated either via specific splice variants of the PAC1-receptor or via an unknown receptor for PACAP-38. In the present study, we characterize degranulation of rat meningeal mast cells in response to PACAP-receptor ligands. Furthermore, we investigate if PACAP-38-induced mast cell degranulation is mediated via PAC1-receptor splice variants and/or via the orphan Mas-related G-protein coupled member B3 (MrgB3)-receptor. To address this, the pharmacological effect of different PACAP isoforms on meningeal mast cell degranulation was investigated in the hemisected skull model after toluidine blue staining followed by microscopic quantification. Presence of mRNA encoding PAC1-receptor splice variants and the MrgB3-receptor in rat mast cells was investigated by Reverse Transcriptase-Polymerase Chain Reaction (RT-PCR) analysis. The effect of PACAP isoforms on PAC1- and MrgB3-receptor-expressing Xenopus laevis oocytes were performed by two-electrode voltage-clamp (TEVC) electrophysiology. PACAP-38 is a more potent mast cell degranulating agent than Pituitary Adenylate Cyclase Activating Peptide-27 (PACAP-27) in the meninges. Presence of mRNA encoding the PAC1-receptor and its different splice variants could not be detected in peritoneal mast cells by RT-PCR, whereas the orphan MrgB3-receptor, recently suggested to be a mediator of basic secretagogues-induced mast cell degranulation, was widely present. In PAC1-receptor-expressing Xenopus laevis oocytes both PACAP-38, PACAP-27 and the specific PAC1-receptor agonist maxadilan were equipotent, however, only PACAP-38 showed a significant degranulatory effect on mast cells. We confirmed Pituitary Adenylate Cyclase Activating Peptide(6–38) [PACAP(6–38)] to be a PAC1-receptor antagonist, and we demonstrated that it is a potent mast cell degranulator and have an agonistic effect on MrgB3-receptors expressed in oocytes. The present study provides evidence that PACAP-induced mast cell degranulation in rat is mediated through a putative new PACAP-receptor with the order of potency being: PACAP-38 = PACAP(6–38) > > PACAP-27 = maxadilan. The results suggest that the observed responses are mediated via the orphan MrgB3-receptor