title: Calcium-activated potassium current modulates ventricular repolarization in chronic heart failure.
abstract: The role of I(KCa) in cardiac repolarization remains controversial and varies across species. The relevance of the current as a therapeutic target is therefore undefined. We examined the cellular electrophysiologic effects of I(KCa) blockade in controls, chronic heart failure (HF) and HF with sustained atrial fibrillation. We used perforated patch action potential recordings to maintain intrinsic calcium cycling. The I(KCa) blocker (apamin 100 nM) was used to examine the role of the current in atrial and ventricular myocytes. A canine tachypacing induced model of HF (1 and 4 months, n = 5 per group) was used, and compared to a group of 4 month HF with 6 weeks of superimposed atrial fibrillation (n = 7). A group of age-matched canine controls were used (n = 8). Human atrial and ventricular myocytes were isolated from explanted end-stage failing hearts which were obtained from transplant recipients, and studied in parallel. Atrial myocyte action potentials were unchanged by I(KCa) blockade in all of the groups studied. I(KCa) blockade did not affect ventricular myocyte repolarization in controls. HF caused prolongation of ventricular myocyte action potential repolarization. I(KCa) blockade caused further prolongation of ventricular repolarization in HF and also caused repolarization instability and early afterdepolarizations. SK2 and SK3 expression in the atria and SK3 in the ventricle were increased in canine heart failure. We conclude that during HF, I(KCa) blockade in ventricular myocytes results in cellular arrhythmias. Furthermore, our data suggest an important role for I(KCa) in the maintenance of ventricular repolarization stability during chronic heart failure. Our findings suggest that novel antiarrhythmic therapies should have safety and efficacy evaluated in both atria and ventricles.
authors.affiliation: College of Pharmacy, The Ohio State University, Columbus, Ohio, United States of America; Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus, Ohio, United States of America.
authors.forename: Ingrid M
authors.initials: IM
authors.lastname: Bonilla
authors.affiliation: College of Pharmacy, The Ohio State University, Columbus, Ohio, United States of America; Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus, Ohio, United States of America.
authors.forename: Victor P
authors.initials: VP
authors.lastname: Long
authors.affiliation: College of Veterinary Medicine, The Ohio State University, Columbus, Ohio, United States of America.
authors.forename: Pedro
authors.initials: P
authors.lastname: Vargas-Pinto
authors.affiliation: Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus, Ohio, United States of America.
authors.forename: Patrick
authors.initials: P
authors.lastname: Wright
authors.affiliation: Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus, Ohio, United States of America.
authors.forename: Andriy
authors.initials: A
authors.lastname: Belevych
authors.affiliation: Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus, Ohio, United States of America.
authors.forename: Qing
authors.initials: Q
authors.lastname: Lou
authors.affiliation: St Jude Medical, Sylmar, California, United States of America.
authors.forename: Kent
authors.initials: K
authors.lastname: Mowrey
authors.affiliation: College of Pharmacy, The Ohio State University, Columbus, Ohio, United States of America.
authors.forename: Jae
authors.initials: J
authors.lastname: Yoo
authors.affiliation: Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus, Ohio, United States of America.
authors.forename: Philip F
authors.initials: PF
authors.lastname: Binkley
authors.affiliation: Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus, Ohio, United States of America.
authors.forename: Vadim V
authors.initials: VV
authors.lastname: Fedorov
authors.affiliation: Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus, Ohio, United States of America.
authors.forename: Sandor
authors.initials: S
authors.lastname: Györke
authors.affiliation: Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus, Ohio, United States of America.
authors.forename: Paulus M L
authors.initials: PM
authors.lastname: Janssen
authors.affiliation: Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus, Ohio, United States of America.
authors.forename: Ahmet
authors.initials: A
authors.lastname: Kilic
authors.affiliation: Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus, Ohio, United States of America.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Mohler
authors.affiliation: College of Pharmacy, The Ohio State University, Columbus, Ohio, United States of America; College of Veterinary Medicine, The Ohio State University, Columbus, Ohio, United States of America.
authors.forename: Cynthia A
authors.initials: CA
authors.lastname: Carnes
mesh_terms: D000200:Action Potentials / Q000502:physiology*; D000818:Animals; D001281:Atrial Fibrillation / Q000378:metabolism / Q000503:physiopathology*; D002118:Calcium / Q000378:metabolism*; D004195:Disease Models, Animal; D004285:Dogs; D006321:Heart / Q000503:physiopathology; D006333:Heart Failure / Q000378:metabolism / Q000503:physiopathology*; D006352:Heart Ventricles / Q000378:metabolism / Q000503:physiopathology; D006801:Humans; D009206:Myocardium / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000378:metabolism; D011188:Potassium / Q000378:metabolism*
chemical_list: D011188:Potassium; D002118:Calcium