Determinates of Dantrolene Inhibition of Ryanodine Receptors

Determinates of Dantrolene Inhibition of Ryanodine Receptors

Abstracts EuroSCORE 0.594 (0.545-0.643), EuroSCORE II 0.546 (0.4980.595) and STS Score 0.584 (0.535-0.634). Conclusion: New AF after CABG was common,...

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Abstracts

EuroSCORE 0.594 (0.545-0.643), EuroSCORE II 0.546 (0.4980.595) and STS Score 0.584 (0.535-0.634). Conclusion: New AF after CABG was common, and associated with prolonged hospital stay, but was modestly and suboptimally predicted by AF and cardiac surgery risk models. More accurate scores need to be developed to guide clinical practice. http://dx.doi.org/10.1016/j.hlc.2017.06.272 272 Determinates of Dantrolene Inhibition of Ryanodine Receptors D. Laver 1,∗ , Y. Oo 1 , K. Walweel 1 , D. van Helden 1 , C. dos Remedios 2 , P. Molenaar 3 , B. Knollmann 4 1 School

of Biomedical Sciences, University of Newcastle and Hunter Medical Research Institute, Newcastle, Australia 2 Bosch Institute, Discipline of Anatomy, University of Sydney, Sydney, Australia 3 School of Medicine, University of Queensland, Brisbane, Australia 4 Department of Medicine, Vanderbilt University Medical Centre, Nashville, USA Dantrolene is a neutral hydantoin that is clinically used as a skeletal muscle relaxant to prevent RyR1 over activation in response to volatile anaesthetics. Previously we found that dantrolene produces up to a 45% inhibition of sheep RyR2 an IC50 of 100 nM and that this inhibition requires CaM. In this study, we examine the effect of dantrolene on human RyR2 that are isolated from healthy human donor hearts and hearts with ischaemic cardiomyopathy (ICM) with ethics approval (UoN H-2009-0369; Univ Sydney #2012/2814; QUT EC28114) and incorporated into lipid bilayers. We found that RyR2 from healthy human hearts were not inhibited by dantrolene at concentrations up to 10 ␮M whereas for RyR2 from human hearts with ICM, dantrolene caused a 40% reduction in open probability. Hyper-phosphorylating these RyR2 channels with PKA prior to experiments abolished the effect of dantrolene. The effect of dantrolene in sheep ryR2 was abolished by prior exposure of RyR2 to FK506, a compound known to dissociate FKBP12.6 from the RyR2 complex. This suggests that in addition to CaM, FKBP12.6 is necessary for dantrolene inhibition of RyR2. http://dx.doi.org/10.1016/j.hlc.2017.06.273 273 Diagnosis of Long QT Syndrome Triggered by Domperidone Use for Breast-Feeding D. Blusztein, S. Peters ∗ , S. Joshi Royal Melbourne Hospital, Melbourne, Australia A 36-year-old lady presented with suspected seizure. She is G1P1 after delivering three months earlier and is currently breastfeeding. Her only medication is domperidone

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to assist with breast-milk production. The patient had four previous events concerning seizure activity since the age of 14 with investigations non-diagnostic. Previous triggers included sleep deprivation, alcohol and cocaine use. Her phenotype involved loss of consciousness, behavioural arrest and jerking. She has no family history of sudden death. Her sister has a history suggestive of seizures including one during pregnancy. The patient was brought in by ambulance after waking from a nap disorientated. She called her partner, sounding confused and incoherent, and he subsequently called an ambulance. She had been sleep-deprived in recent days. Initial rhythm with the ambulance was atrial fibrillation. CT brain, electroencephalography and echocardiogram were unremarkable. On spontaneous reversion to sinus rhythm, sinus bradycardia with a prolonged QT interval was noted (500-540ms) and persisted despite cessation of domperidone. Whilst on telemetry, she developed pre-syncope. This correlated with recurrent short runs of polymorphic ventricular tachycardia (VT) initiated by the typical sequence of short-long-short R-R intervals, suggestive of long QT (LQT) syndrome. Atenolol was started and she was referred for genetic testing, revealing both her and her sister have LQT type 2 (LQT2) syndrome (KCNH2 gene). She received an implantable cardioverter defibrillator. Conclusion: This is a novel case of domperidone triggering polymorphic VT and leading to the diagnosis of LQT2 syndrome. http://dx.doi.org/10.1016/j.hlc.2017.06.274 274 Diagnosis of Obstructive Sleep Apnoea in Patients Presenting with Nocturnal Pauses May Prevent the Unnecessary Insertion of Permanent Pacemakers C. Pham ∗ , I. Subiakto, B. Abu Baker, U. Mohamed Northern Health, Melbourne, Australia Introduction: Obstructive sleep apnoea (OSA) is a common medical condition with an estimated prevalence of around 7% worldwide. Patients with OSA have an increased risk of cardiovascular morbidity and mortality. Previous studies have shown a higher incidence of cardiac arrhythmias in OSA. Case Report: We report a 37-year-old male who presented with a significant syncope episode while driving a motor vehicle. His cardiac risk factors include obesity (BMI = 54.1 kg/m2 ), diabetes and tobacco consumption. He reported two similar syncopal episodes over the last twenty years. Transthoracic echocardiogram and baseline ECG were unremarkable for structural heart disease and conduction disorder. Twenty-four hour Holter monitor however, revealed significant nocturnal pauses lasting up to 7.56 seconds. He had a loop recorder (Medtronic Reveal LINQ LNQ 11) confirming episodes of significant nocturnal pauses which diminished after commencing CPAP for the co-diagnosis of severe sleep apnoea as part of the investigation of his symptoms.