<?xml version="1.0" encoding="UTF-8"?><xml><records><record><source-app name="Biblio" version="7.x">Drupal-Biblio</source-app><ref-type>17</ref-type><contributors><authors><author><style face="normal" font="default" size="100%">Arvanitis, DA</style></author><author><style face="normal" font="default" size="100%">Vafiadaki, E.</style></author><author><style face="normal" font="default" size="100%">Johnson, D. M.</style></author><author><style face="normal" font="default" size="100%">Kranias, EG</style></author><author><style face="normal" font="default" size="100%">Sanoudou, D.</style></author></authors></contributors><titles><title><style face="normal" font="default" size="100%">The Histidine-Rich Calcium Binding Protein in Regulation of Cardiac Rhythmicity</style></title><secondary-title><style face="normal" font="default" size="100%">Front PhysiolFront PhysiolFront Physiol</style></secondary-title><alt-title><style face="normal" font="default" size="100%">Frontiers in physiology</style></alt-title><short-title><style face="normal" font="default" size="100%">Frontiers in physiologyFrontiers in physiology</style></short-title></titles><dates><year><style  face="normal" font="default" size="100%">2018</style></year></dates><volume><style face="normal" font="default" size="100%">9</style></volume><pages><style face="normal" font="default" size="100%">1379</style></pages><isbn><style face="normal" font="default" size="100%">1664-042X (Print)1664-042X (Linking)</style></isbn><language><style face="normal" font="default" size="100%">eng</style></language><abstract><style face="normal" font="default" size="100%">Sudden unexpected cardiac death (SCD) accounts for up to half of all-cause mortality of heart failure patients. Standardized cardiology tools such as electrocardiography, cardiac imaging, electrophysiological and serum biomarkers cannot accurately predict which patients are at risk of life-threatening arrhythmic episodes. Recently, a common variant of the histidine-rich calcium binding protein (HRC), the Ser96Ala, was identified as a potent biomarker of malignant arrhythmia triggering in these patients. HRC has been shown to be involved in the regulation of cardiac sarcoplasmic reticulum (SR) Ca(2+) cycling, by binding and storing Ca(2+) in the SR, as well as interacting with the SR Ca(2+) uptake and release complexes. The underlying mechanisms, elucidated by studies at the molecular, biochemical, cellular and intact animal levels, indicate that transversion of Ser96 to Ala results in abolishment of an HRC phosphorylation site by Fam20C kinase and dysregulation of SR Ca(2+) cycling. This is mediated through aberrant SR Ca(2+) release by the ryanodine receptor (RyR2) quaternary complex, due to the impaired HRC/triadin interaction, and depressed SR Ca(2+) uptake by the sarco/endoplasmic reticulum Ca(2+) ATPase (SERCA2) pump, due to the impaired HRC/SERCA2 interaction. Pharmacological intervention with KN-93, an inhibitor of Ca(2+)/calmodulin-dependent protein kinase II (CaMKII), in the HRC Ser96Ala mouse model, reduced the occurrence of malignant cardiac arrhythmias. Herein, we summarize the current evidence on the pivotal role of HRC in the regulation of cardiac rhythmicity and the importance of HRC Ser96Ala as a genetic modifier for arrhythmias in the setting of heart failure.</style></abstract><accession-num><style face="normal" font="default" size="100%">30319456</style></accession-num><notes><style face="normal" font="default" size="100%">Arvanitis, Demetrios AVafiadaki, ElizabethJohnson, Daniel MKranias, Evangelia GSanoudou, DespinaengReviewSwitzerland2018/10/16 06:00Front Physiol. 2018 Sep 27;9:1379. doi: 10.3389/fphys.2018.01379. eCollection 2018.</style></notes><custom2><style face="normal" font="default" size="100%">6171002</style></custom2><auth-address><style face="normal" font="default" size="100%">Molecular Biology Division, Biomedical Research Foundation, Academy of Athens, Athens, Greece.Department of Cardiothoracic Surgery, Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht, Netherlands.Department of Pharmacology and Systems Physiology, University of Cincinnati College of Medicine, Cincinnati, OH, United States.Clinical Genomics and Pharmacogenomics Unit, 4th Department of Internal Medicine, Attikon Hospital, Medical School, National and Kapodistrian University of Athens, Athens, Greece.</style></auth-address></record></records></xml>